JP2023522065A - Pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition comprising an active pharmaceutical ingredient having a calculated octanol-water logP value of about 4.0 or greater, at least one solubilizer, and optionally at least one stratum corneum penetration enhancer, for topical administration A pharmaceutical composition is provided that can be formulated for use. In some cases, the active pharmaceutical ingredient is clofazimine. [Selection drawing] Fig. 1

Description

Cross-reference to related applications
[0001] This application claims the benefit of PCT Application No. PCT/CN2020/085241, filed April 17, 2020, which is hereby incorporated by reference in its entirety.

[0002] Lipophilic active pharmaceutical ingredients, such as clofazimine, have limited solubility in aqueous conditions. Therefore, adsorption and bioavailability of lipophilic components can be limited by their dissolution. Examples of lipophilic active pharmaceutical ingredients include hesperetin, lormetazepam, naringenin, cinchonidine, alprenolol, propranolol, ketoprofen, clofibric acid, clofazimine, naproxen, warfarin, apigenin, diazepam, quinine, quetiapine, rosiglitazone, clotiazepam, tramadol, fenbufen, chlorphenamine, pyrilamine, venlafaxine, brompheniramine, diphenhydramine, chrysin, valsartan, penbutolol, diltiazem, ibuprofen, bupivacaine, flurbiprofen, progesterone, chlordiazepoxide, trazodone, haloperidol, glimepiride, abiraterone, indomethacin, clopidogrel, flurazepam, duloxetine, nortriptyline, celecoxib, nilotinib, atorvastatin, maprotiline, fluoxetine, diclofenac, amitriptyline, imipramine, loratadine, cyproheptadine, chlorpromazine, sertraline, flufenamic acid, miconazole, and rimonabant.

[0003] One exemplary lipophilic component is clofazimine, chemical name N,5-bis(4-chlorophenyl)-3-propan-2-yliminophenazin-2-amine. Clofazimine is a fat-soluble, brick-red phenazine pigment. It is an anti-infective agent with antimycobacterial activity.
_{C27H22Cl2N4 _ _ _}
molecular weight = 473.40
pKa = 8.37
Log P = 7.48
Water solubility = 0.225 mg/L
(virtually insoluble)
Clofazimine Orally administered clofazimine (in combination with rifampicin and dapsone) is the first-line treatment for leprosy, with a high rate of definitive cure after 1-3 years of treatment. Clofazimine was approved for use in the United States in 1986, withdrawn in 2016, and is currently available only under the auspices of the National Hansen's Disease Program. Clofazimine, marketed under the trade name Lamprene, is available as 50 mg soft capsules containing beeswax, butylated hydroxytoluene, citric acid, ethyl vanillin, gelatin, glycerin, iron oxide, lecithin, p-methoxy It also contains acetophenone, parabens, vegetable oil, propylene glycol, and clofazimine dispersed as micron-sized particles. According to FDA label information, the absorption of clofazimine varies from 45-62%. Observing the effect of food after oral administration, the time to reach peak plasma concentrations (T _max ) was reduced from 12 hours to 8 hours under fed conditions compared to fasting conditions. The prescription is to take Lamprene with food.

[0004] The exact mechanism by which clofazimine acts is unknown. However, it preferentially binds to mycobacterial DNA, inhibiting DNA replication and cell proliferation. It also increases the activity of bacterial phospholipase A2, which causes the release and accumulation of lysophospholipids that are toxic and inhibit bacterial growth.

[0005] The major side effects of clofazimine include skin discoloration and painful gastrointestinal disturbances, nausea and diarrhea. The skin discoloration is due to clofazimine's reddish-orange color, with pinkish-brown discoloration of the skin and body fluids in the majority of patients treated for more than one month. The discoloration disappears when the drug is stopped, but may persist for months or years. Gastrointestinal side effects of clofazimine are severe and may require dose modification or discontinuation. Symptoms appear to be due to crystallization of clofazimine molecules in the intestinal submucosa; these crystals may also be found in the liver, lymph nodes, and spleen. The possible cause of liver injury from clofazimine therapy is unknown and may be related to the formation of drug crystals in hepatic macrophages. Clofazimine crystals may be found in the liver and spleen of patients undergoing long-term therapy, but do not appear to be associated with overt liver damage.

[0006] Clofazimine also exhibits immunosuppressive and anti-inflammatory activity. Clofazimine is a Kv1.3 blocker. The KCNA3 gene encodes the potassium voltage-gated channel Kv1.3 (or KCNA3) protein expressed in T and B lymphocytes and plays an important role in the activation and proliferation of T lymphocyte effector memory (TEM) cells. Fulfill. Selective suppression of effector memory T cells by Kv1.3-specific blockers addresses many autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, type 1 diabetes) without compromising protective immune responses. can be done. In proof-of-concept studies, Kv1.3 blockers prevented and treated disease in rat models of multiple sclerosis, type 1 diabetes, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity. In human clinical studies, the majority of patients showed remission upon treatment of chronic discoid lupus erythematosus with clofazimine. Other clinical studies show clofazimine's promise in the treatment of other autoimmune diseases such as psoriasis and Mischa's granulomatous cheilitis.

[0007] Topical formulations are often preferred for the treatment of skin disorders. However, the body's natural protective layer, the outer layer of the skin (stratum corneum), significantly impedes drug penetration. Despite the therapeutic success of clofazimine described above, topical formulations are not available. Clofazimine is remarkably hydrophobic, posing challenges to development as a topical formulation for clinical use.

[0008] Accordingly, there is a need for pharmaceutical compositions comprising clofazimine formulated for topical administration. More generally, there is a need for improved formulations of highly lipophilic active pharmaceutical ingredients, eg for topical administration. There is an unmet need to provide therapeutics to treat, prevent, reduce the severity of, reduce the incidence of, delay the onset of, or alleviate the etiology of skin diseases, including psoriasis.
Inclusion by reference
[0009] All publications and patent applications mentioned herein are incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. incorporated herein.

[0010] In one aspect, stable topical formulations comprising a lipophilic active pharmaceutical ingredient, such as the APIs of Table 1, are described herein. It has been discovered by the inventors of the present disclosure that the topical pharmaceutical formulations described herein improve the chemical and physical stability of APIs.

[0011] Provided herein are pharmaceutical compositions and methods of using the compositions for the treatment of disease. In one aspect, provided herein are topical pharmaceutical compositions, wherein (a) an active pharmaceutical ingredient (API) or pharmaceutical composition thereof is present in an amount of up to about 2% of the total weight of the composition. API or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a calculated logP in octanol-water of about 4.0 or greater; and (b) at least one solubilization A pharmaceutical composition comprising an agent and formulated for topical administration. In some embodiments, the API or pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. In one aspect, provided herein are topical pharmaceutical compositions, wherein (a) an active pharmaceutical ingredient (API) or a API or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a calculated logP in octanol-water of about 4.0 or greater; and (b) at least one A pharmaceutical composition comprising a solubilizing agent, wherein the API or a pharmaceutically acceptable salt thereof is dissolved in at least one solubilizing agent and formulated for topical administration. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount up to about 5% or 2% of the total weight of the composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount up to about 1.5% of the total weight of the composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount up to about 1% of the total weight of the composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.001% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.1% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.005% to about 0.5% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 0.5% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.1% to about 0.2% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.1% to about 0.5% of the total weight of the pharmaceutical composition. In some embodiments, the API is hesperetin, lormetazepam, naringenin, cinchonidine, alprenolol, propranolol, ketoprofen, clofibric acid, naproxen, warfarin, apigenin, diazepam, quinine, quetiapine, rosiglitazone, clotiazepam, tramadol, fenbufen, chlorphenamine, pyrilamine, venlafaxine, brompheniramine, diphenhydramine, chrysin, valsartan, penbutolol, diltiazem, ibuprofen, bupivacaine, flurbiprofen, progesterone, chlordiazepoxide, trazodone, haloperidol, glimepiride, abiraterone, indomethacin, clopidogrel, flurazepam, duloxetine, nortriptyline, celecoxib, nilotinib, atorvastatin, maprotiline, fluoxetine, diclofenac, amitriptyline, imipramine, loratadine, cyproheptadine, chlorpromazine, sertraline, flufenamic acid, miconazole or rimonabant. In some embodiments, the API has a calculated logP in octanol-water of about 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5 or greater . In some embodiments, the API provides a calculated logP in octanol-water within the range of about 4.0, 4.5, 5.0, 5.5 or 6 to about 7, 8, 9 or 10. have. In some embodiments, pharmaceutical compositions are non-aqueous. In one aspect, provided herein are topical pharmaceutical compositions, wherein (a) a compound, or a pharmaceutically acceptable salt thereof, is present in an amount up to about 2% of the total weight of the composition wherein the compound has the formula (I):

(In the formula,
Each of R ¹ , R ² and R ³ is independently an aryl radical selected from the group consisting of phenyl, chlorophenyl, lower alkylphenyl and lower alkoxyphenyl; C ₁ -C ₁₂ alkyl; C ₃ -C ₈ cyclo alkyl; or C ₁ -C ₁₁ heteroalkyl, wherein each of aryl, alkyl, cycloalkyl, and heteroalkyl is substituted or unsubstituted;
R ₄ represents a hydrogen atom or a halogen atom;
R ₅ represents a hydrogen atom or a halogen atom)
A compound or a pharmaceutically acceptable salt thereof having the structure of;
and (b) a pharmaceutical composition comprising at least one solubilizer and formulated for topical administration.

In some embodiments, the compound or pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. In one aspect, provided herein are topical pharmaceutical compositions, wherein (a) a compound or pharmaceutically acceptable a salt of the formula (I):

(In the formula,
Each of R ¹ , R ² and R ³ is independently an aryl radical selected from the group consisting of phenyl, chlorophenyl, lower alkylphenyl and lower alkoxyphenyl; C ₁ -C ₁₂ alkyl; C ₃ -C ₈ cyclo alkyl; or C ₁ -C ₁₁ heteroalkyl, wherein each of aryl, alkyl, cycloalkyl, and heteroalkyl is substituted or unsubstituted;
R ₄ represents a hydrogen atom or a halogen atom;
R ₅ represents a hydrogen atom or a halogen atom)
A compound or a pharmaceutically acceptable salt thereof having the structure of;
and (b) comprising at least one solubilizing agent, wherein the compound or a pharmaceutically acceptable salt thereof is dissolved in the at least one solubilizing agent, and the pharmaceutical composition is formulated for topical administration. A pharmaceutical composition. In some embodiments, R ¹ is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. In some embodiments, R ³ is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. In some embodiments, ^R2 is an ethyl, propyl, butyl, pentyl, hexyl, heptyl, decyl, cyclohexyl, or cycloheptyl radical. In some embodiments, R ² is ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, heptyl, 1,3-dimethylbutyl, sec-butyl, 1,1-dimethylethyl (t-butyl), 3,5,5-trimethylpentyl, n-dodecyl, n-decyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,5-dimethylcyclohexyl, or cycloheptyl radicals. In some embodiments, each of R ⁴ and R ⁵ is hydrogen. In some embodiments, the compound is clofazimine, 2-(p-chloro-anilino)-3-cyclohexylimino-5-(p-chlorophenyl)-3,5-dihydro-phenazine, 2-anilino-3-cyclohexyl It is imino-5-phenyl-3,5-dihydrophenazine. In some embodiments, the compound or pharmaceutically acceptable salt thereof is clofazimine. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount up to about 1.5% of the total weight of the composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount up to about 1% of the total weight of the composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount from about 0.001% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.1% of the total weight of the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof is present in an amount from about 0.1% to about 0.5% of the total weight of the pharmaceutical composition. In some embodiments, pharmaceutical compositions are non-aqueous. In some embodiments, the at least one solubilizer comprises: (i) saturated hydrocarbons or mixtures thereof; (ii) fatty alcohols having at least 9 carbons; (iii) at least 9 carbons; containing one or more of the fatty acids that have In some embodiments, at least one solubilizer comprises saturated hydrocarbons or mixtures thereof. In some embodiments, the at least one solubilizer is: (i) petroleum jelly; (ii) one or more alkanes each independently having at least 9 carbons; (iii) at least 9 and (iv) fatty acids with at least 9 carbons. In some embodiments, the at least one solubilizer is (i) petroleum jelly, (ii) one or more alkanes each independently having at least 9 carbons, and (iii) Contains carbon-bearing fatty alcohols. In some embodiments, the solubilizer is present in an amount from about 50% to about 99% of the total weight of the pharmaceutical composition. In some embodiments, the solubilizer is present in an amount from about 80% to about 99% of the total weight of the pharmaceutical composition. In some embodiments, the solubilizer is present in an amount from about 80% to about 99.9% of the total weight of the pharmaceutical composition. In some embodiments, at least one solubilizing agent comprises petroleum jelly. In some embodiments, petroleum jelly is present in an amount from about 20% to about 99% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 20% to about 99.9% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 70% to about 95% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 80% to about 90% of the total weight of the pharmaceutical composition. In some embodiments, the petroleum jelly comprises about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88% of the total weight of the pharmaceutical composition; about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% is present in an amount of In some embodiments, the at least one solubilizer comprises one or more alkanes each independently having at least 9 carbons. In some embodiments, the one or more alkanes is nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, tetracosane, or nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, and tetracosane, each independently linear or branched, including combinations is. In some embodiments, the one or more alkanes include nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, or combinations thereof, including nonane, decane, undecane, dodecane, tridecane, tetradecane, Pentadecane and hexadecane are each independently linear or branched. In some embodiments, the one or more alkanes is liquid paraffin. In some embodiments, one or more alkanes are present in an amount from about 0.5% to about 30% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 2% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 5% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, the one or more alkanes is about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5% of the total weight of the pharmaceutical composition. %, about 8%, about 8.5%, about 9%, about 9.5%, or about 10%. In some embodiments, the one or more alkanes is about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4% of the total weight of the pharmaceutical composition, Present in an amount of about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, or about 9%. In some embodiments, at least one solubilizer comprises a fatty alcohol having at least 9 carbons. In some embodiments, the fatty alcohol is 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 , 29, 30, 31, 32, 33, or 34 carbon alcohols. In some embodiments, fatty alcohols include alcohols with 12-24 carbons. In some embodiments, the fatty alcohol is fully saturated or partially saturated. In some embodiments, the fatty alcohol is stearyl alcohol. In some embodiments, the fatty alcohol is present in an amount from about 0.1% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, the fatty alcohol is present in an amount from about 1% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, the fatty alcohol is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5% of the total weight of the pharmaceutical composition. %, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8%. In some embodiments, at least one solubilizer comprises a fatty acid having at least 9 carbons. In some embodiments, the fatty acid is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, Contains 29, 30, 31, 32, 33, or 34 carbons. In some embodiments, the at least one solubilizer is (i) petroleum jelly in an amount from about 20% to about 99% of the total weight of the pharmaceutical composition, (ii) about liquid paraffin in an amount from 0.5% to about 30%; and (iii) optionally stearyl alcohol in an amount from about 0.1% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, the at least one solubilizing agent comprises petroleum jelly in an amount from about 20% to about 99.9% of the total weight of the pharmaceutical composition. In some embodiments, the at least one solubilizing agent comprises petroleum jelly in an amount from about 20% to about 99.9% of the total weight of the pharmaceutical composition. In some embodiments, the compound is clofazimine and the at least one solubilizer is (i) petroleum jelly in an amount from about 70% to about 99% of the total weight of the pharmaceutical composition, and (ii) Liquid paraffin in an amount of about 0.5% to about 30% of the total weight of the pharmaceutical composition. In some embodiments, the compound is clofazimine and the at least one solubilizer is (i) petroleum jelly in an amount from about 70% to about 99.9% of the total weight of the pharmaceutical composition, and ( ii) optionally comprising liquid paraffin in an amount from about 0.5% to about 30% of the total weight of the pharmaceutical composition; In some embodiments, the pharmaceutical composition comprises a stratum corneum penetration enhancer. In some embodiments, the stratum corneum penetration enhancer is polyethoxylated sorbitan monooleate, laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or combinations thereof. In some embodiments, the stratum corneum penetration enhancer is lecithin. In some embodiments, the stratum corneum penetration enhancer is present in an amount from about 1% to about 20% of the total weight of the pharmaceutical composition. In some embodiments the pharmaceutical composition is formulated as a cream. In some embodiments the pharmaceutical composition is formulated as a gel. In some embodiments, formulations described herein are stable formulations. In some embodiments, the formulation retains about 90 to about 110% w/w of the initial amount of the compound or pharmaceutically acceptable salt thereof after being stored at 40° C. and 75% RH for 6 months. do. In some embodiments, the formulation retains about 90 to about 110% w/w of the initial amount of the compound or pharmaceutically acceptable salt thereof after being stored at 25° C. and 60% RH for 9 months. do. In some embodiments, the formulation is stored at 25° C. or 40° C. for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months. about 90% to about 110% w/w of the initial amount of compound or pharmaceutically acceptable salt thereof. In some embodiments, the formulation is stored at 25° C. or 40° C. for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months. about 95% to about 105% w/w of the initial amount of compound or pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the pharmaceutical compositions provided herein are gels. In some embodiments, a pharmaceutical composition provided herein is a cream. In some embodiments, pharmaceutical compositions provided herein are for topical administration.

[0013] Further provided herein is an active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a logP calculation in octanol-water of about 4.0 or greater at least one solubilizer; and optionally at least one stratum corneum penetration enhancer, which can be formulated for topical administration. composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 10.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 5.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.75% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.25% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.1% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.001% to about 10.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 5.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 2.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 0.1% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.05% to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.1% to about 0.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 3.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 3.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 4.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 4.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 5.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 6.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 6.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 7.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 7.5. Further provided herein are pharmaceutical compositions wherein the API logP is from about 4.0 to about 10.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 5.0 to about 9.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 6.0 to about 8.5. Further provided herein are pharmaceutical compositions wherein the API logP is from about 6.5 to about 8.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 7.0 to about 8.0. In some embodiments, the API is hesperetin, lormetazepam, naringenin, cinchonidine, alprenolol, propranolol, ketoprofen, clofibric acid, naproxen, warfarin, apigenin, diazepam, quinine, quetiapine, rosiglitazone, clotiazepam, tramadol, fenbufen, chlorphenamine, pyrilamine, venlafaxine, brompheniramine, diphenhydramine, chrysin, valsartan, penbutolol, diltiazem, ibuprofen, bupivacaine, flurbiprofen, progesterone, chlordiazepoxide, trazodone, haloperidol, glimepiride, abiraterone, indomethacin, clopidogrel, flurazepam, duloxetine, nortriptyline, celecoxib, nilotinib, atorvastatin, maprotiline, fluoxetine, diclofenac, amitriptyline, imipramine, loratadine, cyproheptadine, chlorpromazine, sertraline, flufenamic acid, miconazole or rimonabant. Further provided herein is that the solubilizer is PEG 400, alcohols, polyoxyethylene sorbitan monooleate, polyethers, ethers, glycol ethers, octyl/decyl mono- and diglycerides, pegylated fatty acid glycerides, fatty acids, fatty acids A pharmaceutical composition that is an ester, or any combination thereof. Further provided herein are pharmaceutical compositions wherein the solubilizer is one or more glycol ethers. Further provided herein are pharmaceutical compositions wherein the solubilizer is a glycol ether. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-(2-ethoxyethoxy)ethanol. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is Transcutol. Further provided herein are lecithin, ethanol, octanol, oleic acid, SDS, DMSO, polyoxyethylene sorbitan monooleate (eg sold under the trademark Tween®), such as polyoxyethylene (20) A pharmaceutical composition which is sorbitan monooleate and polyoxyethylene (80) sorbitan monooleate, laurocapram, phospholipids, pegylated fatty acid glycerides, or combinations thereof. Further provided herein are pharmaceutical compositions wherein the stratum corneum penetration enhancer is a phospholipid. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin isolated from egg yolk. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin isolated from soybean. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises phosphatidylcholine.

[0014] Further provided herein is a topical formulation comprising clofazimine, or a pharmaceutically acceptable salt thereof; at least one solubilizer; and, optionally, at least one stratum corneum penetration enhancer. Pharmaceutical compositions that can be formulated for administration. Further provided herein is a pharmaceutical composition wherein clofazimine, or a pharmaceutically acceptable salt thereof, constitutes up to about 5.0% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein clofazimine, or a pharmaceutically acceptable salt thereof, constitutes up to about 1.0% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine or a pharmaceutically acceptable salt thereof constitutes up to about 0.75% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine or a pharmaceutically acceptable salt thereof constitutes up to about 0.5% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine, or a pharmaceutically acceptable salt thereof, constitutes up to about 0.25% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine or a pharmaceutically acceptable salt thereof constitutes up to about 0.1% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein clofazimine, or a pharmaceutically acceptable salt thereof, comprises from about 0.01% to about 5.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein clofazimine, or a pharmaceutically acceptable salt thereof, comprises from about 0.01% to about 2.5% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine, or a pharmaceutically acceptable salt thereof, comprises about 0.01% to about 0.1% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein clofazimine, or a pharmaceutically acceptable salt thereof, comprises about 0.01% to about 1.0% of the total weight of the composition. Further provided herein is a pharmaceutical composition wherein clofazimine or a pharmaceutically acceptable salt thereof comprises from about 0.05% to about 1.0% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein clofazimine, or a pharmaceutically acceptable salt thereof, comprises about 0.1% to about 0.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizer comprises up to about 60% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises up to about 50% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the solubilizer comprises up to about 40% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the solubilizer comprises up to about 35% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the solubilizer comprises up to about 30% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the solubilizer comprises up to about 25% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises up to about 20% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises from about 1% to about 60% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises from about 5% to about 50% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the solubilizer comprises from about 5% to about 35% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises from about 10% to about 40% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises from about 10% to about 30% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the solubilizing agent comprises from about 15% to about 25% of the total weight of the composition. Further provided herein is that the solubilizer is PEG 400, alcohols, polyoxyethylene sorbitan monooleate, ethers, polyethers, glycol ethers, octyl monodiglycerides, decyl monodiglycerides, octyl/decyldiglycerides, PEG A pharmaceutical composition that is hydrogenated fatty acid glycerides, fatty acids, fatty acid esters, or any combination thereof. Further provided herein are pharmaceutical compositions wherein the solubilizer is a glycol ether. Further provided herein is that the solubilizer is 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol, 2-phenoxyethanol, 2-benzyloxyethanol ethanol, 1-methoxy-2-propanol, 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol, 2-(2-propoxyethoxy)ethanol, 2-(2-butoxyethoxy)ethanol, A pharmaceutical composition which is (2-methoxyethoxy)methanol, (2-ethoxyethoxy)methanol, (2-propoxyethoxy)methanol, or (2-butoxyethoxy)methanol. Further provided herein is that the solubilizing agent is 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol, 2-(2-propoxyethoxy)ethanol, or 2-( 2-butoxyethoxy) ethanol. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-(2-methoxyethoxy)ethanol. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-(2-ethoxyethoxy)ethanol. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-(2-propoxyethoxy)ethanol. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-(2-butoxyethoxy)ethanol. Further provided herein are pharmaceutical compositions wherein the solubilizing agent is dimethoxyethane, diethoxyethane, dipropoxyethane, or dibutoxyethane. Further provided herein is a pharmaceutical composition, wherein the solubilizing agent is 2-methoxyethyl acetate, 2-ethoxyethyl acetate, 2-butoxyethyl acetate, or 1-methoxy-2-propanol acetate be. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 30% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 20% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 15% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 10% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 5% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 4% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 3% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises up to about 2% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer constitutes up to about 1% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 1% to about 30% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 1% to about 20% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 2% to about 19% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 1% to about 15% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 1% to about 10% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 2% to about 8% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 3% to about 7% of the total weight of the composition. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer comprises from about 4% to about 6% of the total weight of the composition. Further provided herein are polyoxyethylene sorbitan monooleate (eg, sold under the trademark Tween®), laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or A pharmaceutical composition that is a combination. Further provided herein are pharmaceutical compositions wherein the stratum corneum penetration enhancer is a phospholipid. Further provided herein are pharmaceutical compositions wherein the stratum corneum penetration enhancer is phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin, lecithin, or phosphatidic acid. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin isolated from egg yolk. Further provided herein is a pharmaceutical composition, wherein the stratum corneum penetration enhancer is lecithin isolated from soybean.

[0015] Further provided herein are from about 0.001% to about 2% by weight clofazimine, or a pharmaceutically acceptable salt thereof; from about 5 to about 50% by weight solubilized and from about 1 to about 20% by weight of a stratum corneum penetration enhancer. Further provided herein are from about 0.01% to about 2% by weight of clofazimine, or a pharmaceutically acceptable salt thereof; from about 5% to about 50% by weight of a solubilizer. and from about 1% to about 20% by weight of a stratum corneum penetration enhancer. Further provided herein is clofazimine, or a pharmaceutically acceptable salt thereof, present in an amount from about 0.01% to about 2.0% of the total weight of the composition; A pharmaceutical composition comprising 2-(2-ethoxyethoxy)ethanol present in an amount from about 10% to about 30% by weight; and lecithin present in an amount from about 2% to about 19% by total weight of the composition. It is a thing. Further provided herein is clofazimine, or a pharmaceutically acceptable salt thereof, present in an amount of about 0.1% to about 0.5% of the total weight of the composition; A pharmaceutical composition comprising 2-(2-ethoxyethoxy)ethanol present in an amount from about 15% to about 25% by weight; and lecithin present in an amount from about 4% to about 6% by total weight of the composition. It is a thing. Further provided herein is clofazimine, or a pharmaceutically acceptable salt thereof, present in an amount of about 0.1% of the total weight of the composition; an amount of about 20% of the total weight of the composition; and lecithin present in an amount of about 5% of the total weight of the composition. Further provided herein is an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a calculated logP in octanol-water of 4.0 or greater. or a pharmaceutically acceptable salt thereof; 2-(2-ethoxyethoxy)ethanol; and lecithin, which can be formulated for topical administration. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 10.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 5.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.75% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.25% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API constitutes up to about 0.1% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 10.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 5.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 2.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.01% to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.05% to about 1.0% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the API comprises from about 0.1% to about 0.5% of the total weight of the composition. Further provided herein are pharmaceutical compositions wherein the logP of the API is greater than about 2.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 3.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 3.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 4.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 4.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 5.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 6.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 6.5. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 7.0. Further provided herein are pharmaceutical compositions wherein the API logP is greater than about 7.5. Further provided herein are pharmaceutical compositions wherein the API logP is from about 4.0 to about 10.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 5.0 to about 9.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 6.0 to about 8.5. Further provided herein are pharmaceutical compositions wherein the API logP is from about 6.5 to about 8.0. Further provided herein are pharmaceutical compositions wherein the API logP is from about 7.0 to about 8.0.

[0016] Further provided herein is an API, or a pharmaceutically acceptable salt thereof, present in an amount from about 0.01% to about 2.0% of the total weight of the composition; a solubilizer present in an amount from about 5% to about 50% of the total weight of the composition; and a stratum corneum penetration enhancer present in an amount from about 1% to about 20% of the total weight of the composition. composition. Further provided herein is an API, or a pharmaceutically acceptable salt thereof, present in an amount from about 0.01% to about 2.0% of the total weight of the composition; A pharmaceutical composition comprising 2-(2-ethoxyethoxy)ethanol present in an amount from about 10% to about 30% by weight; and lecithin present in an amount from about 2% to about 19% by total weight of the composition. It is a thing. Further provided herein is an API, or a pharmaceutically acceptable salt thereof, present in an amount from about 0.1% to about 0.5% of the total weight of the composition; A pharmaceutical composition comprising 2-(2-ethoxyethoxy)ethanol present in an amount from about 15% to about 25% by weight; and lecithin present in an amount from about 4% to about 6% by total weight of the composition. It is a thing.

[0017] In some embodiments, the formulations described herein are stable formulations. In some embodiments, the formulation retains about 90 to about 110% w/w of the initial amount of the compound or pharmaceutically acceptable salt thereof after being stored at 40° C. and 75% RH for 6 months. do. In some embodiments, the total amount of impurities in the formulation after storage at 40° C. and 75% RH for 6 months is 2% w/ w or less. In some embodiments, when stored at about 40° C. and 75% RH for 6 months, the formulation assays between 90% and 110% w/w based on the initial amount of API. In some embodiments, when stored at about 25° C. and 60% RH for 9 months, the formulation assays between 90% and 110% w/w based on the initial amount of API. In some embodiments, when stored at about 40° C. and 75% RH for 6 months, the formulation has a total amount of impurities of about 2% w/w or less, based on the initial amount of API. In some embodiments, when stored at about 25° C. and 60% RH for 9 months, the formulation has a total amount of impurities of about 2% w/w or less, based on the initial amount of API. In some embodiments, the compositions of the formulations described herein degrade by less than 2% when held at 60° C. for 3 days. In some embodiments, the compositions of the formulations described herein degrade by less than 1% when held at 60° C. for 3 days. In some embodiments, the compositions of the formulations described herein degrade by less than 0.5% when held at 60° C. for 3 days. In some embodiments, the compositions of the formulations described herein degrade by less than 1% when kept at 23° C. for 9 months. In some embodiments, the compositions of the formulations described herein degrade by less than 0.5% when kept at 23° C. for 9 months. In some embodiments, the compositions of the formulations described herein degrade by less than 0.2% when kept at 23° C. for 9 months.

[0018] Further provided herein are pharmaceutical compositions further comprising a preservative. In some embodiments, the preservative is calcium benzoate, chlorobutanol, nipalgin or sorbate. In some embodiments, the preservative is calcium benzoate. In some embodiments, the preservative is chlorobutanol. In some embodiments, the preservative is nipalgin. In some embodiments, the preservative is sorbate.

[0019] Further provided herein are methods for treating skin disorders. Further provided herein are methods for treating skin disorders comprising administering the pharmaceutical compositions described herein. Further provided herein is the use of the described pharmaceutical composition in the preparation of a medicament for treating skin disorders. In some embodiments, the skin disease is caused by inflammation. In some embodiments, the skin disease is caused by immune inflammation. In some embodiments, the skin disease is psoriasis, vitiligo, lupus erythematosus, chronic eczema, dermatitis or contact dermatitis. In some embodiments, the skin disease is psoriasis. In some embodiments, the skin disorder is vitiligo. In some embodiments, the skin disease is lupus. In some embodiments, the skin disease is lupus erythematosus. In some embodiments, the skin disease is eczema or chronic eczema. In some embodiments, the skin disease is dermatitis or contact dermatitis.

[0020] The novel features of the disclosure are pointed out with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure may be obtained by reference to the following detailed description and accompanying drawings, which set forth illustrative embodiments in which the principles of the present disclosure are employed.

[0021] Figure 1 shows the effect of various solvents (PEG 400, Transcutol, Tween (Tween) 20, Tween 80, Laurocapram, oleic acid, ethanol and KHS-15) on the percutaneous permeation of clofazimine. is a bar graph showing. The X-axis indicates solvent type and the Y-axis indicates clofazimine content in μg/cm ² . [0022] Figure 2 is a bar graph showing the effect of various solvents (PEG 400, Transcutol, Tween 80 and labrasol) on clofazimine skin permeation. The X-axis indicates solvent type and the Y-axis indicates clofazimine content in μg/cm ² . [0023] Figure 3 is a bar graph showing the effect of various solvents (PEG 400, Transcutol, Tween 80 and labrasol) on skin permeation of clofazimine in gel and solution matrices. The X-axis indicates solvent type and the Y-axis indicates clofazimine content in μg/cm ² . [0024] Figure 4 is a bar graph showing the effect of various penetration enhancers on skin permeation of clofazimine. The X-axis indicates the type of penetration enhancer and the Y-axis indicates the clofazimine content in μg/cm ² . [0025] Figure 5 is a bar graph showing the effect of lecithin concentration on skin permeation of clofazimine. The X-axis shows percent lecithin concentration and the Y-axis shows clofazimine content in μg/cm ² . [0026] Figure 6 is a bar graph showing the effect of pH on skin permeation of clofazimine in gel formulations. The X-axis shows pH and the Y-axis shows clofazimine content in μg/cm ² . [0027] Figure 7 is a bar graph showing the effect of clofazimine concentration on skin permeation of clofazimine. The X-axis shows percent clofazimine concentration and the Y-axis shows clofazimine content in μg/cm ² . [0028] Figure 8 is a bar graph showing the effect of gelling agent (carbomer carbomer 940) concentration on clofazimine skin permeation. The X-axis shows percent carbomer 940 concentration and the Y-axis shows clofazimine content in μg/cm ² . [0029] Figure 9 is a cartoon representation of the apparatus used to determine the skin permeability of various clofazimine preparations described in Example 4; [0030] Figure 10 is a bar graph showing that permeation of clofazimine through the stratum corneum increases with clofazimine concentration in topical creams as long as the clofazimine is completely dissolved in the formulation. The X-axis indicates the formulations tested and the Y-axis indicates the clofazimine content in the endothelium in μg/cm ² . [0031] Figure 11 shows the results of a study comparing inhibition of IL-2 secretion of activated Jurkat cells treated with clofazimine as described in Example 22.

[0032] The present disclosure generally includes pharmaceutically active agents useful as therapeutics to alleviate, alleviate or eliminate one or more conditions in a subject in need of treatment, as further described herein Compositions. In particular, pharmaceutical compositions, their preparation and use are described herein, wherein the pharmaceutical composition comprises a lipophilic API, at least one solubilizer, and at least one stratum corneum penetration enhancer. Included in combination, the API therefore has improved bioavailability compared to the API alone.

definition
[0033] Unless specifically stated otherwise or clear from context, as used herein, the term "about" in relation to a number or range of numbers refers to one or more of the stated numbers. +/- 10% of, ie, 10% less than the lower recited limit and 10% greater than the upper recited limit for any recited value in a range.

[0034] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "surfactant" includes reference to one or more specific surfactants, and reference to "antioxidant" includes one or more such additives. contains a reference to

[0035] As used herein, the term "subject" refers to a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human animal such as a monkey, chimpanzee, or baboon). human primates).

[0036] "Effective amount" and "sufficient amount" can be used interchangeably and refer to a sufficient amount of a substance to achieve its intended purpose or goal.

[0037] A "therapeutically effective amount" when used in reference to the pharmaceutical compositions described herein is one or more pharmaceutical actives sufficient to produce a therapeutic result in a subject in need of treatment. is the amount of agent.

[0038] "Therapeutically equivalent" when used in reference to the pharmaceutical compositions described herein refers to a pharmaceutically active agent that is equivalent to a therapeutically effective amount of the free base of the pharmaceutically active agent or alcohol. refers to the amount or quantity of a pharmaceutically acceptable salt or ester of

[0039] The definitions provided herein apply regardless of whether the terms in question appear alone or in combination. In addition to the definitions provided herein to form chemically related combinations such as "heterocycloalkylaryl", "haloalkylheteroaryl", "arylalkylheterocycloalkyl", or "alkoxyalkyl" It is considered possible. The final member of the combination is the radical attached to the rest of the molecule. The other members of the combination are attached to the linking radicals in the opposite order with respect to letter sequence, for example the combination arylalkylheterocycloalkyl is heterocycloalkyl substituted by alkyl substituted by aryl. - refers to radicals.

[0040] Terms such as "substituted," "substituent," and the like, unless otherwise indicated, include halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, oxo, thioxy, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl when referring to the replacement of one or more hydrogen radicals in a given structure by radicals of specified substituents including, but not limited to, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic groups. There is It is understood that substituents may be further substituted.

[0041] The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from a group of possible substituents. means When indicating the number of substituents, the term "one or more" means from one substituent to as many substitutions as possible, i.e. from the replacement of one hydrogen by a substituent to the replacement of all hydrogens. do.

[0042] The term "alkane" refers to a hydrocarbon of the formula _{CnH2n +2} , where n is an integer greater than or equal to 1. Alkanes are linear or branched. It should be understood that isomers of alkanes are encompassed by the term "alkane." As used herein, C ₁ -C _x (or C _1-x ) are C ₁ -C ₂ , C ₁ -C ₃ . . . Including C ₁ -C _x . By way of example only, a group designated “C ₁ -C ₄ ” has from 1 to 4 carbon atoms in the moiety, i.e. 1 carbon atom, 2 carbon atoms, 3 carbon atoms Atoms or groups containing 4 carbon atoms. Thus, by way of example only, “C ₁ -C ₄ alkyl” means that the alkyl group has 1-4 carbon atoms, ie the alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec -butyl, and t-butyl.

[0043] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (ie, an arylene group). Unless otherwise stated herein, the term "aryl" or the prefix "ar-" (such as "aralkyl") is meant to include optionally substituted aryl groups. In some embodiments, aryl groups are partially reduced to form cycloalkyl groups as defined herein. In some embodiments, aryl groups are fully reduced to form cycloalkyl groups as defined herein.

[0044] The term "alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 20 carbon atoms and attached to the remainder of the molecule by a single bond. An alkyl containing up to 10 carbon atoms is called a C ₁ -C ₁₀ alkyl, similarly an alkyl containing, for example, up to 6 carbon atoms is a C ₁ -C ₆ alkyl or lower alkyl. Alkyl (and other moieties defined herein) containing other numbers of carbon atoms are represented similarly. Alkyl groups include C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ - Examples include, but are not limited to, C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₂ -C ₈ alkyl, C ₃ -C ₈ alkyl, and C ₄ -C ₈ alkyl. Representative alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t -butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like, but are not limited to these. In some embodiments, alkyl is methyl or ethyl. In some embodiments, alkyl is -CH(CH ₃ ) ₂ or -C(CH ₃ ) ₃ . Unless stated otherwise specifically in the specification, alkyl groups may be optionally substituted as described below. "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group. In some embodiments, alkylene is -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -. In some embodiments, alkylene is -CH ₂ -. In some embodiments, alkylene is -CH ₂ CH ₂ -. In some embodiments, alkylene is -CH ₂ CH ₂ CH ₂ -.

[0045] The term "alkoxy" refers to a radical of the formula -OR, where R is a defined alkyl radical. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, alkoxy is methoxy. In some embodiments, alkoxy is ethoxy.

[0046] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (ie, backbone atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocycles or bridged compounds. In some embodiments, a cycloalkyl is fused to an aromatic ring (where the cycloalkyl is attached through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include cycloalkyls having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. include but are not limited to: Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, monocyclic cycloalkyl is cyclopentenyl. @ Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetranyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, Spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. Unless stated otherwise specifically in the specification, a cycloalkyl group may be optionally substituted.

[0047] The term "haloalkyl" means an alkyl group wherein at least one of the alkyl group's hydrogen atoms has been replaced with the same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl are monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl , fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" means an alkyl group in which all hydrogen atoms of the alkyl group have been replaced with the same or different halogen atoms.
Active Pharmaceutical Ingredient (API)
[0048] Various embodiments described herein are directed to compositions comprising an effective amount of an active pharmaceutical agent (API). "Active pharmaceutical agent", "API", "drug", "pharmaceutically active agent", "bioactive agent", "therapeutic agent", and "active agent" etc. can be used interchangeably and effective amounts refers to a substance, such as a compound or complex, that, when administered, produces a measurable beneficial physiological effect in the body, such as a therapeutic effect in the treatment of a disease or disorder. Furthermore, where these terms are used, or where a particular active agent is specifically identified by name or category, such descriptions refer to the active agent itself as well as its pharmaceutically acceptable pharmacological derivatives active in or compounds significantly related thereto, including but not limited to salts, pharmaceutically acceptable salts, N-oxides, esters, prodrugs, active metabolites, isomers, fragments, analogs , solvates, hydrates, radioisotopes and the like.

[0049] The partition coefficient (P) as referred to herein is the ratio of the concentrations of a compound between two immiscible solvent phases at equilibrium. Most commonly one of the solvents is water and the other is hydrophobic, usually 1-octanol. The logarithm of the ratio is log P (usually the lipophilic phase is the numerator and the hydrophilic phase is the denominator) as shown below.

[0050] logP is a measure of lipophilicity or hydrophobicity. Hydrophobicity affects drug absorption, bioavailability, hydrophobic drug-receptor interactions, molecule metabolism, and toxicity. Hydrophilic compounds are soluble in water (“water-loving”) and soluble in polar solvents. Lipophilic compounds are sparingly soluble in water (“water-afraid” or hydrophobic) and sparingly soluble in polar solvents, but more soluble in organic solvents. therefore:
Low hydrophilic = high lipophilic = high log P = poor absorption High hydrophilic = low lipophilic = low log P = good absorption
[0051] Those skilled in the art are familiar with Lapinsky's rule of five, which suggests that in order for compounds to have a reasonable chance of being fully absorbed, their logP must be less than 5.0. five).

[0052] Partition coefficients can be measured experimentally or estimated by calculation. Various methods have been developed to calculate (or predict) logP, usually by fitting the calculated logP value to experimentally measured logP values for a training set of thousands of mostly drug-like molecules. by letting The logP calculation is considered very robust and accurately handles many organic molecules. For example, more than 50% of the numerators in logP are predicted with an error of less than 0.25 and more than 80% are predicted with an error of less than 0.5. Structures predicted with an error greater than 1.0 are less than 3.5%. LogP calculations are sometimes denoted as clogP to distinguish them from logP measurements.

[0053] In some embodiments, the API is lipophilic. In some embodiments, the API is insoluble in polar solvents. In some embodiments, the API is insoluble in aqueous media. In some embodiments, the API is water insoluble.

[0054] In some embodiments, the API has a calculated logP value of at least 2.5. In some embodiments, the API has a calculated logP value of at least 2.6. In some embodiments, the API has a calculated logP value of at least 2.7. In some embodiments, the API has a calculated logP value of at least 2.8. In some embodiments, the API has a calculated logP value of at least 2.9. In some embodiments, the API has a calculated logP value of at least 3.0. In some embodiments, the API has a calculated logP value of at least 3.1. In some embodiments, the API has a calculated logP value of at least 3.2. In some embodiments, the API has a calculated logP value of at least 3.3. In some embodiments, the API has a calculated logP value of at least 3.4. In some embodiments, the API has a calculated logP value of at least 3.5. In some embodiments, the API has a calculated logP value of at least 3.6. In some embodiments, the API has a calculated logP value of at least 3.7. In some embodiments, the API has a calculated logP value of at least 3.8. In some embodiments, the API has a calculated logP value of at least 3.9. In some embodiments, the API has a calculated logP value of at least 4.0. In some embodiments, the API has a calculated logP value of at least 4.1. In some embodiments, the API has a calculated logP value of at least 4.2. In some embodiments, the API has a calculated logP value of at least 4.3. In some embodiments, the API has a calculated logP value of at least 4.4. In some embodiments, the API has a calculated logP value of at least 4.5. In some embodiments, the API has a calculated logP value of at least 4.6. In some embodiments, the API has a calculated logP value of at least 4.7. In some embodiments, the API has a calculated logP value of at least 4.8. In some embodiments, the API has a calculated logP value of at least 4.9. In some embodiments, the API has a calculated logP value of at least 5.0. In some embodiments, the API has a calculated logP value of at least 5.1. In some embodiments, the API has a calculated logP value of at least 5.2. In some embodiments, the API has a calculated logP value of at least 5.3. In some embodiments, the API has a calculated logP value of at least 5.4. In some embodiments, the API has a calculated logP value of at least 5.5. In some embodiments, the API has a calculated logP value of at least 5.6. In some embodiments, the API has a calculated logP value of at least 5.7. In some embodiments, the API has a calculated logP value of at least 5.8. In some embodiments, the API has a calculated logP value of at least 5.9. In some embodiments, the API has a calculated logP value of at least 6.0. In some embodiments, the API has a calculated logP value of at least 6.1. In some embodiments, the API has a calculated logP value of at least 6.2. In some embodiments, the API has a calculated logP value of at least 6.3. In some embodiments, the API has a calculated logP value of at least 6.4. In some embodiments, the API has a calculated logP value of at least 6.5. In some embodiments, the API has a calculated logP value of at least 6.6. In some embodiments, the API has a calculated logP value of at least 6.7. In some embodiments, the API has a calculated logP value of at least 6.8. In some embodiments, the API has a calculated logP value of at least 6.9. In some embodiments, the API has a calculated logP value of at least 7.0. Exemplary small molecule APIs with calculated logP greater than 2.0 include, but are not limited to, those listed in Table 1.

[0055] The acid dissociation constant, Ka (or acidity constant), is a measure of the strength of an acid in solution, usually water. This is the equilibrium constant for chemical dissociation of acids. In aqueous solutions, the acid dissociation equilibrium is written as:

In the formula, HA is an acid that dissociates into A ⁻ (the conjugate base of the acid) and hydrogen ions (which combine with water molecules to create hydronium ions, H ₃ O ⁺ ). The dissociation constant can also be written with H ₂ O omitted:

[0056] _pKa , the logarithmic value of _Ka , is more often used to express the strength/weakness of an acid:
pK _a =−log ₁₀ (K _a )
A more positive pK _a value indicates a lower degree of dissociation and a weaker acid. in general:
pK _a =-2 to 12 → weak acid (mostly or only partially dissociated in water)
pKa <-2 → strong acid (completely or almost dissociated in water)
[0057] In some embodiments, the APIs described herein are weak bases. In some embodiments, the API comprises weakly basic functional groups. In some embodiments, the API has a pKa of 3.0 or greater. In some embodiments, the API has a pKa of 3.5 or greater. In some embodiments, the API has a pKa of 4.0 or greater. In some embodiments, the API has a pKa of 4.5 or greater. In some embodiments, the API has a pKa of 5.0 or greater. In some embodiments, the API has a pKa of 5.5 or greater. In some embodiments, the API has a pKa of 6.0 or greater. In some embodiments, the API has a pKa of 6.5 or greater. In some embodiments, the API has a pKa of 7.0 or greater. In some embodiments, the API has a pKa of 7.5 or greater. In some embodiments, the API has a pKa of 8.0 or greater.

[0058] In some embodiments, the APIs described herein are present in free base form. In some embodiments, the API is present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium, magnesium and the like; organic amine salts such as triethylamine and pyridine salts. , picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.; inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc. organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates; and amino acid salts such as, but not limited to, alginate, aspartate, glutamate, and the like. Pharmaceutically acceptable salts include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate. , pentafluoropropionate, hydrobromide, mucate, oleate, dibasic phosphate, monobasic phosphate, acetate trihydrate, bis(heptafluorobutyrate), Further included are bis(pentafluoropropionate), bis(pyridinecarboxylate), bis(trifluoroacetate), hydrochloride, and sulfate pentahydrate. Other representative pharmaceutically acceptable salts include, for example, water-soluble and water-insoluble salts such as acetates, amsonates (4,4-diaminostilbene-2,2-disulfonate), benzene Sulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulanic acid Salts (clavulariate), dihydrochloride, edetate, edisylate, estolate, esylic acid, fiunarate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanyl phosphate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide salt, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide salt, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2 - naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/ Diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, acetate, succinate, sulfate, sulfosalicylate, suramate ), tannates, tartrates, teocrates, tosylates, triethiozides, and valerates. Hydrates are another example of pharmaceutically acceptable salts. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the APIs described herein constitute from about 0.0001% to about 50% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.001% to about 10% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API is from about 0.001%, 0.005%, 0.01%, 0.05%, or 0.1% of the total weight of the pharmaceutical compositions described herein. make up up to about 0.2%, 0.5%, 1%, 2%, or 5%. In some embodiments, the API constitutes from about 0.001% to about 2.5% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.005% to about 1% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.05% to about 1% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.01% to about 1% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.01% to about 0.5% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.01% to about 2% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes from about 0.01% to about 0.05% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the API constitutes about 0.01% of the total weight of the composition. In some embodiments, API constitutes about 0.02% of the total weight of the composition. In some embodiments, the API constitutes about 0.025% of the total weight of the composition. In some embodiments, the API constitutes about 0.03% of the total weight of the composition. In some embodiments, API constitutes about 0.04% of the total weight of the composition. In some embodiments, the API constitutes about 0.05% of the total weight of the composition. In some embodiments, API constitutes about 0.06% of the total weight of the composition. In some embodiments, API constitutes about 0.07% of the total weight of the composition. In some embodiments, API constitutes about 0.075% of the total weight of the composition. In some embodiments, API constitutes about 0.08% of the total weight of the composition. In some embodiments, API constitutes about 0.09% of the total weight of the composition. In some embodiments, the API constitutes about 0.1% of the total weight of the composition. In some embodiments, API constitutes about 0.11% of the total weight of the composition. In some embodiments, API constitutes about 0.12% of the total weight of the composition. In some embodiments, API constitutes about 0.125% of the total weight of the composition. In some embodiments, API constitutes about 0.13% of the total weight of the composition. In some embodiments, the API constitutes about 0.14% of the total weight of the composition. In some embodiments, API constitutes about 0.15% of the total weight of the composition. In some embodiments, API constitutes about 0.16% of the total weight of the composition. In some embodiments, API constitutes about 0.17% of the total weight of the composition. In some embodiments, API constitutes about 0.175% of the total weight of the composition. In some embodiments, API constitutes about 0.18% of the total weight of the composition. In some embodiments, API constitutes about 0.19% of the total weight of the composition. In some embodiments, API constitutes about 0.20% of the total weight of the composition. In some embodiments, the API constitutes about 0.25% of the total weight of the composition. In some embodiments, the API constitutes about 0.3% of the total weight of the composition. In some embodiments, API constitutes about 0.35% of the total weight of the composition. In some embodiments, the API constitutes about 0.4% of the total weight of the composition. In some embodiments, API constitutes about 0.45% of the total weight of the composition. In some embodiments, the API constitutes about 0.5% of the total weight of the composition. In some embodiments, the API constitutes about 0.6% of the total weight of the composition. In some embodiments, API constitutes about 0.7% of the total weight of the composition. In some embodiments, API constitutes about 0.8% of the total weight of the composition. In some embodiments, the API constitutes about 0.9% of the total weight of the composition. In some embodiments, the API constitutes about 1% of the total weight of the composition. In some embodiments, the API constitutes about 1.1% of the total weight of the composition. In some embodiments, the API constitutes about 1.2% of the total weight of the composition. In some embodiments, API constitutes about 1.3% of the total weight of the composition. In some embodiments, API constitutes about 1.4% of the total weight of the composition. In some embodiments, the API constitutes about 1.5% of the total weight of the composition. In some embodiments, the API constitutes about 1.6% of the total weight of the composition. In some embodiments, API constitutes about 1.7% of the total weight of the composition. In some embodiments, API constitutes about 1.8% of the total weight of the composition. In some embodiments, API constitutes about 1.9% of the total weight of the composition. In some embodiments, the API constitutes about 2% of the total weight of the composition. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, and optionally a penetration enhancer. In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API with a clogP greater than 4, a solubilizer with a solubility of the API with a clogP greater than 4, and optionally a penetration enhancer . In some embodiments, the API solubility in the solubilizer is at least 0.1 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 0.5 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 3 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 4 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 5 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 6 mg/mL. In some embodiments, the solubility of the API in the solubilizer is at least 7 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 8 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 9 mg/mL. In some embodiments, the solubility of the API in the solubilizer is at least 10 mg/mL. In some embodiments, the solubility of the API in the solubilizer is at least 11 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 12 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 13 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 14 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 15 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 20 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 25 mg/mL. In some embodiments, the API solubility in the solubilizer is at least 50 mg/mL. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, described herein are pharmaceutical compositions comprising an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof, and at least one solubilizer. and the compound has the formula (I):

(In the formula,
Each of R ¹ , R ² and R ³ is independently an aryl radical selected from the group consisting of phenyl, chlorophenyl, lower alkylphenyl and lower alkoxyphenyl; C ₁ -C ₁₂ alkyl; C ₃ -C ₈ cyclo alkyl; or C ₁ -C ₁₁ heteroalkyl, wherein each of aryl, alkyl, cycloalkyl, and heteroalkyl is substituted or unsubstituted;
R ₄ represents a hydrogen atom or a halogen atom;
R ₅ represents a hydrogen atom or a halogen atom)
A pharmaceutical composition having the structure

In some embodiments, the compound or pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. In some embodiments, pharmaceutical compositions are formulated for topical administration. In some embodiments, R ¹ is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. In some embodiments, R ³ is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. In some embodiments, both R ¹ and R ³ are selected from phenyl, chlorophenyl, lower alkylphenyl, and lower alkoxyphenyl, wherein phenyl, chlorophenyl, lower alkylphenyl, and lower alkoxyphenyl are substituted or unsubstituted is. In some embodiments, each of R ¹ and R ³ is independently an ethyl, propyl, butyl, pentyl, hexyl, heptyl, decyl, cyclohexyl, or cycloheptyl radical. In some embodiments, ^R2 is an ethyl, propyl, butyl, pentyl, hexyl, heptyl, decyl, cyclohexyl, or cycloheptyl radical. In some embodiments, R ² is ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, heptyl, 1,3-dimethylbutyl, sec-butyl, 1,1-dimethylethyl (t-butyl), 3,5,5-trimethylpentyl, n-dodecyl, n-decyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,5-dimethylcyclohexyl, or cycloheptyl radicals. In some embodiments, each of R ⁴ and R ⁵ is hydrogen. In some embodiments, the compound is clofazimine, 2-(p-chloro-anilino)-3-cyclohexylimino-5-(p-chlorophenyl)-3,5-dihydro-phenazine, 2-anilino-3-cyclohexyl It is imino-5-phenyl-3,5-dihydrophenazine. In some embodiments, the compound is clofazimine.
Solubilizer/Solubilizer/Solvent
[0062] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, and optionally a penetration enhancer. Dissolving agent, or solubilizing agent or solvent, or other similar terms known to those of skill in the art, refers to an agent or combination of agents that solubilizes or partially solubilizes an API, as described herein. point to In some embodiments, the pharmaceutical composition comprises a lipophilic API with a clogP greater than 4, a solvent having a solubility of the API with a clogP greater than 4, and a penetration enhancer.

[0063] In one aspect, described herein are topical pharmaceutical compositions comprising an active pharmaceutical ingredient (API) (such as clofazimine) or a pharmaceutically acceptable salt thereof and at least one solubilizer is. In some embodiments, described herein is an API or pharmaceutically acceptable salt thereof present in an amount from about 0.001% to about 10% of the total weight of the composition. an API or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a calculated logP in octanol-water of about 4.0 or greater; and from about 20% to about 99.999 of the total weight of the composition A topical pharmaceutical composition comprising at least one solubilizing agent present in an amount up to %. In some embodiments, the pharmaceutical composition is a non-aqueous composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. In some embodiments, polarized light microscopy can be used to determine whether the API is dissolved in at least one solubilizer. In some embodiments, the API has a calculated logP in octanol-water of about 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5 or greater . In some embodiments, the API provides a calculated logP in octanol-water within the range of about 4.0, 4.5, 5.0, 5.5 or 6 to about 7, 8, 9 or 10. have. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 5% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.001% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.1% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 2% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, the API or pharmaceutically acceptable salt thereof is present in an amount from about 0.1% to about 0.5% of the total weight of the pharmaceutical composition.

[0064] In some embodiments, described herein are clofazimine, or a pharmaceutically acceptable and at least one solubilizing agent present in an amount from about 20% to about 99.999% of the total weight of the composition. In some embodiments, the pharmaceutical composition is a non-aqueous composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. In some embodiments, the clofazimine or pharmaceutically acceptable salt thereof is clofazimine. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 5% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 2% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 1% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.1% to about 0.5% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.1% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.2% of the total weight of the pharmaceutical composition. In some embodiments, clofazimine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% of the total weight of the pharmaceutical composition.

[0065] In some embodiments, the solubilizer is an amide, ester, alcohol such as ethanol, isopropanol, butanol, benzyl alcohol, polyol, polyvinyl alcohol, ethylene glycol, propylene glycol, polypropylene glycol, butanediol, propylene. Glycol ether, glycerol, glyceride, fatty acid, fatty acid ester, fatty acid glyceride, polyethylene glycol fatty acid ester, vegetable oil, oleic acid, castor oil, diethylene glycol ether, PEGylated glyceride, 2-(2-ethoxyethoxy) ethanol (Transcutol), PEG400, Polyoxyethylene sorbitan monooleate (such as those sold under the trademark Tween®), KHS-15, laurocapram (i.e. N-dodecylcaprolactam or 1-dodecylazepan-2-one), penta erythritol, sorbitol, mannitol, dimethylisosorbide, hydroxypropylmethylcellulose and other cellulose derivatives, maltodextrins, cyclodextrins, cyclodextrin derivatives, isomers thereof or combinations thereof.

[0066] In some embodiments, the solubilizer is fatty acid, glyceride, vegetable oil, oleic acid, pegylated glyceride, 2-(2-ethoxyethoxy) ethanol (Transcutol), PEG400, polyoxyethylene (20) sorbitan monooleates (for example, sold under the trademark Tween-20®), polyoxyethylene (80) sorbitan monooleate (sold under the trademark Tween-80®), ethanol , KHS-15, laurocapram (ie, N-dodecylcaprolactam or 1-dodecylazepan-2-one) (eg, sold under the trademark Azone®), or combinations thereof. In some embodiments, the solubilizing agent comprises laurocapram. In some embodiments, the solubilizing agent comprises ethanol. In some embodiments, the solubilizing agent comprises Transcutol. In some embodiments, the solubilizing agent comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the solubilizer comprises a weight percent of about 1% to about 50% of the composition. In some embodiments, the solubilizer is about 1% to about 3%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% of the composition. to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 1% to about 40%, about 1% to about 45%, about 1% to about 50%, about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, about 3% to about 20%, about 3% to about 25%, about 3% to about 30% , about 3% to about 35%, about 3% to about 40%, about 3% to about 45%, about 3% to about 50%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35% , about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, or about 45% to about 50%. In some embodiments, the solubilizer comprises about 1%, about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% of the composition. , about 40%, about 45%, or about 50% by weight. In some embodiments, the solubilizer is at least about 1%, about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% of the composition. %, about 40%, or about 45%. In some embodiments, the solubilizer comprises up to about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% of the composition. %, about 45%, or about 50%.

[0068] In some embodiments, Transcutol comprises a weight percent of about 1% to about 50% of the composition. In some embodiments, Transcutol is about 1% to about 3%, about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 1% to about 40%, about 1% to about 45%, about 1% to about 50% , about 3% to about 5%, about 3% to about 10%, about 3% to about 15%, about 3% to about 20%, about 3% to about 25%, about 3% to about 30%, about 3% to about 35%, about 3% to about 40%, about 3% to about 45%, about 3% to about 50%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40% , about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40% , about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, or about 45% to about 50%. In some embodiments, Transcutol is about 1%, about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about constitute a weight percentage of 40%, about 45%, or about 50%. In some embodiments, Transcutol is at least about 1%, about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% of the composition; make up a weight percentage of about 40%, or about 45%. In some embodiments, Transcutol comprises up to about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% of the composition; make up a weight percentage of about 45%, or about 50%.

[0069] In some embodiments, the pharmaceutical formulations described herein comprise one or more fatty acids or derivatives thereof. Exemplary fatty acids include carboxylic acids consisting of a hydrocarbon chain and a terminal carboxy (-COOH) group. The hydrocarbon chain may be saturated (containing no carbon-carbon double bonds) or unsaturated, such as monounsaturated (containing one carbon-carbon double bond) or polyunsaturated (multiple carbon-carbon containing a double bond). Fatty acids can contain carbon chains that are straight (or unbranched) carbon chains or can contain branched carbon chains. In some embodiments, the one or more fatty acids are C ₉ -C ₂₀ fatty acids, C ₉ -C ₁₂ fatty acids, C ₉ -C ₁₅ fatty acids, C ₉ -C ₁₈ fatty acids, C ₁₂ -C ₁₈ fatty acids, or containing _C9 - _C32 fatty acids.

[0070] In some embodiments, the pharmaceutical formulations described herein comprise one or more long chain fatty acids, or combinations thereof. In some embodiments, the long chain fatty acid is a carboxylic acid containing at least 12 carbon atoms. In some embodiments, the long chain fatty acid contains at least 11 carbon atoms. In some embodiments, the long chain fatty acid contains at least 12 carbon atoms. In some embodiments, the long chain fatty acid contains at least 13 carbon atoms. In some embodiments, the long chain fatty acid contains at least 14 carbon atoms. In some embodiments, the long chain fatty acid contains at least 15 carbon atoms. In some embodiments, the long chain fatty acid contains at least 16 carbon atoms. In some embodiments, the long chain fatty acid contains at least 17 carbon atoms. In some embodiments, the long chain fatty acid contains at least 18 carbon atoms. In some embodiments, the long chain fatty acid contains at least 19 carbon atoms. In some embodiments, the long chain fatty acid contains at least 20 carbon atoms. Examples of straight chain saturated fatty acids include, but are not limited to, those listed in Table 2. In some embodiments, pharmaceutical formulations described herein comprise one or more fatty acids of Tables 2 and 3.

[0071] Examples of linear unsaturated fatty acids include, but are not limited to, those listed in Table 3.

[0072] In some embodiments, the solubilizing agent comprises a glyceride. Glycerides are fatty acid esters of glycerol.

Glycerides may be monoglycerides, diglycerides, and triglycerides, with glycerol esterified with one, two, or three fatty acids. Other terms of the art for triglycerides include TG's, triacylglycerols, TAG's, triacylglycerides, fats, etc., and are used interchangeably herein. Glycerides can be further modified by substitutions in one or more of the hydrocarbon chains.

[0073] Examples of monoglycerides and diglycerides include monopalmitolein, monoelaidin, monocaproin, monocaprylin, monocaprin, monolaurin, glyceryl monomyristate, glyceryl monooleate, glyceryl monooleate, glycerol monooleate/linoleate, glycerol mono Linoleate, glyceryl ricinoleate, glyceryl monolaurate, glycerol monopalmitate, glycerol monostearate, glyceryl monodiolate, palmitate/glyceryl stearate, glyceryl acetate, glyceryl laurate, glyceryl citrate/lactate/oleate/ linoleate, glyceryl caprylate, glyceryl caprylate/caprate, mono- and di-glycerides caprylic acid, caprylic/capric glycerides, mono- and di-acetylated monoglycerides, glyceryl monostearate, lactate esters of mono- and diglycerides, dicaproin, dicaprin, dioctanoin, Dimyristine, dipalmitin, distearin, glyceryl dilaurate, glyceryl dioleate, glycerol esters of fatty acids, 1,2 and 1,3-diolein, dielaidin, dilinolein, and combinations thereof. Other fatty acids include stearyl alcohol, capric acid, caprylic acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachnidoic acid, behenic acid, and their pharmaceutical counterparts. contains acceptable salts. Preferred fatty acid and fatty alcohol derivatives include sodium dioctylsulfosuccinate, sodium lauryl sulfate, amide esters (e.g. lauric acid diethanolamide, sodium lauryl sarcosinate, lauroylcarnitine, palmitoylcarnitine and myristoylcarnitine), esters with hydroxy acids (e.g. , sodium stearoyl lactylate), sugar esters [e.g., lauryl lactate, glucose monocaprylate, diglucose monocaprylate, sucrose laurate, sorbitan monolaurate (Arlacel® 20), sorbitan monopalmitate (Span-40 ), sorbitan monooleate (Span-80), sorbitan monostearate and sorbitan tristearate, lower alcohol fatty acid esters [e.g. ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), isopropyl palmitate (Crodamol IPP)], esters with propylene glycol [e.g. propylene glycol monolaurate (Lauroglycol FCC)], propylene glycol ricinoleate (Propymuls), propylene glycol monooleate (Myverol® P-06), propylene glycol monocaprylate (Capryol® 90), propylene glycol dicaprylate/dicaprate (Captex® 200) and propylene glycol dioctanoate (Captex 800)], esters with glycerol [e.g. Oleate (Peceol), Glyceryl Ricinoleate, Glyceryl Laurate, Glyceryl Dilaurate (Capmul® GDL), Glyceryl Dioleate (Capmul GDO), Glycerol Monolinoleate (Maisine®), Glyceryl Mono- / dioleate (Capmul GMO-K), glyceryl caprylate/caprate (Capmul MCM), caprylic acid mono/diglycerides (Imwitor® 988), mono- and di-acetylated monoglycerides (Myvacet® 9-45)], Triglycerides [e.g. corn oil, almond oil, soybean oil, coconut oil, castor oil, hydrogenated castor oil, hydrogenated coconut oil, Pureco 100, Hydrokote AP5, Captex 300, 350, Miglyol 812, Miglyol 818, Gelucire 33/01)] , mixtures of propylene glycol and glycerol esters [e.g. mixtures of oleate esters of propylene glycol and glycerol (Arlacel 186)], and polyglyceryl fatty acids such as polyglyceryl oleate (Plurol® Oleique), polyglyceryl-2 Dioleate (Nikkol DGDO), Polyglyceryl-10 Trioleate, Polyglyceryl-10 Laurate (Nikkol Decaglyn 1-L), Polyglyceryl-10 Oleate (Nikkol Decaglyn 1-O), and Polyglyceryl-10 Mono, Dioleate (Caprol® PEG 860 ).

[0074] Additional fatty acid derivatives include polyethoxylated fatty acids such as PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG- 12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate), PEG-fatty acid diesters (e.g. PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate), PEG-fatty acid mono- and diester mixtures, polyethylene glycol glycerol fatty acid esters (e.g. PEGylated glycerol 12 acyloxystearate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate). PEG-20 glyceryl oleate and PEG-30 glyceryl oleate) and alcohol-oil transesterification products [e.g. Polyoxyl 40 castor oil (Cremophor® RH40), Polyoxyl 35 castor oil (Cremophor EL or Incrocas 35), PEG-25 Trioleate (TAGAT® TO), PEG-60 Corn Glycerides (Crovol M70), PEG-60 Almond Oil (Crovol A70), PEG40 Palm Kernel Oil (Crovol PK70), PEG-50 Castor Oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-60 hydrogenated castor oil (Cremophor RH60), PEG-8 caprylic/capric glycerides (Labrasol®), lauroyl macrogol 32 glycerides (Gelucire® 44/14), linoleoyl macroglycerides (Labrafil®), stearoyl macrogol-32 glycerides (Gelucire 50/13), and PEG-6 caprylic/capric glycerides ( Softigen (registered trademark) 767)].

[0075] Bile acid and sterol derivatives include, but are not limited to, cholate, ursodeoxycholate, chenodeoxycholate, taurochenodeoxycholate, tauroursodeoxycholate, glycokenodeoxycholate, glycoursodeoxycholate, sterols, and , sterol esters or ethers such as PEG-24 cholesterol ether.

[0076] The tocol derivative includes the tocol structure [2-methyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol], or the tocotrienol structure [2-methyl-2-(4,8 , 12-trimethyltrideca-3,7,11-trienyl)chroman-6-ol]. In particular mono-, di- and trimethyl tocols, commonly known as tocopherols, and their organic acid esters such as acetates, nicotinates, succinates and polyethylene glycol succinates. For example, α-tocopherol acetate, α-tocopherol nicotinate, α-tocopherol succinate, α-tocopherol polyethylene glycol succinate (200-8000 Mw), α-tocopherol polyethylene glycol 400 succinate, dl-α-tocopherol polyethylene glycol 1000 succinate, and d-α-tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS, Eastman Chemical Co.). Mixed racemates (eg, any racemate or dl-), as well as pure enantiomers (eg, d-, l- or RRR-) are preferred for the practice of the present disclosure. Preferred tocol derivatives include α-tocopherol esters and polyethoxylated α-tocopherol esters. More specifically preferred tocol derivatives include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinoate, α-tocopherol succinate, α-tocopherol polyethylene glycol succinate, α-tocopherol polyethylene glycol (200- 8000 Mw) succinate, α-tocopherol polyethylene glycol 400 succinate, α-tocopherol polyethylene glycol 1000 succinate, dl-α-tocopherol polyethylene glycol 1000 succinate, or d-α-tocopherol polyethylene glycol 1000 succinate.

[0077] As used herein, the term "long-chain lipid solvent" refers to a pharmaceutically acceptable lipid solvent containing 12 or more carbon atoms. In some embodiments, the long-chain lipid solvent is capable of dissolving therapeutic amounts of APIs. Examples of long chain lipid solvents include, but are not limited to, fatty alcohols, fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, animal oils, pegylated glycerides, vitamin E derivatives, and combinations thereof. In some embodiments, the long chain lipid solvent contains at least 12 carbon atoms.

[0078] In one aspect, the pharmaceutical compositions described herein comprise an API (such as clofazimine) or a pharmaceutically acceptable salt thereof and at least one solubilizer. In some embodiments, the pharmaceutical composition comprises an API selected from Table 1 and the following: (i) petroleum jelly; (ii) one or more alkanes each independently having at least 9 carbons; iii) a fatty alcohol having at least 9 carbons; and (iv) at least one solubilizer comprising one or more of fatty acids having at least 9 carbons. In some embodiments, the at least one solubilizer comprises 1, 2, 3, 4, 5, 6, or more different solubilizers. In some embodiments, the at least one solubilizing agent is: (i) petroleum jelly (i.e. petroleum jelly), (ii) one or more alkanes each independently having at least 9 carbons, ( iii) fatty alcohols having at least 9 carbons; (iv) fatty acids having at least 9 carbons, (v) diols such as propyl glycol, (vi) polyols such as glycerin, (vii) polyethoxylated glycerides, e.g. as polyethoxylated monoglycerides, polyethoxylated diglycerides and/or polyethoxylated triglycerides (e.g. polyethoxylated hydrogenated castor oil sold under the trade name Kolliphor® RH40), (viii) polyethylene glycol, (ix) partially saturated hydrocarbons, or combinations thereof. In some embodiments, the at least one solubilizer comprises a solubilizer described elsewhere herein. In some embodiments, the at least one solubilizer is: (i) petroleum jelly; (ii) one or more alkanes each independently having at least 9 carbons; (iii) at least 9 and (iv) fatty acids with at least 9 carbons. In some embodiments, the at least one solubilizer is one or more of: (i) petroleum jelly, (ii) one or more alkanes each independently having at least 9 carbons , or both.

[0079] In some embodiments, the weight ratio of API (such as clofazimine) or pharmaceutically acceptable salt thereof to the solubilizer described herein is from about 1:10 to Up to about 10,000. In some embodiments, the weight ratio of API (such as clofazimine) or pharmaceutically acceptable salt thereof to the solubilizer described herein is about 1:40, 1:50 in the pharmaceutical composition. , 1:60, 1:70, 1:80, 1:90, or 1:100 to about 1:200, 1:300, 1:400, 1:500, 1:750, 1:1000, 1:2000 , 1:3000, 1:4000, or up to 1:5000. In some embodiments, the weight ratio of API (such as clofazimine) or a pharmaceutically acceptable salt thereof to the solubilizer described herein is about 1:50, 1:70, 1:100, 1:400, 1:1000, 1:2500, or 1:3000.

[0080] In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent, wherein the at least one solubilizing agent comprises petroleum jelly (ie, petrolatum). In some embodiments, the weight ratio of API (such as clofazimine) or pharmaceutically acceptable salt thereof to petroleum jelly is from about 1:50 to about 1:1000 in the pharmaceutical composition. In some embodiments, the weight ratio of API (such as clofazimine) or pharmaceutically acceptable salt thereof to petroleum jelly is from about 1:100 to about 1:250 in the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 20% to about 99% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 50% to about 95% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 70% to about 95% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 70% to about 80% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 80% to about 90% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount from about 90% to about 95% of the total weight of the pharmaceutical composition. In some embodiments, petroleum jelly is present in an amount of about 90% of the total weight of the pharmaceutical composition. In some embodiments, the petroleum jelly comprises about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88% of the total weight of the pharmaceutical composition; about 89%, about 90%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about It is present in an amount of 99.9%.

[0081] In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizer, and at least one solubilizer comprises one or more alkanes. In some embodiments, each of the one or more alkanes independently has at least 9 carbons. In some embodiments, the one or more alkanes is nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, tetracosane, or nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, and tetracosane, each independently linear or branched, including combinations is. In some embodiments, the one or more alkanes include nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, or combinations thereof, including nonane, decane, undecane, dodecane, tridecane, tetradecane, Pentadecane and hexadecane are each independently linear or branched. In some embodiments, the one or more alkanes are in a liquid state at 25°C. In some embodiments, the one or more alkanes are in a liquid state at 50°C. In some embodiments, the one or more alkanes are in a liquid state at 80°C. In some embodiments, the one or more alkanes is liquid paraffin. In some embodiments, one or more alkanes (such as liquid paraffin) are present in an amount from about 0.5% to about 30% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 2% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, the one or more alkanes is from about 1%, 2%, 3%, 4% or 5% to about 6%, 7%, 8%, 9% of the total weight of the pharmaceutical composition. , 10%, 11%, 12%, 13%, 14%, 15% or 20%. In some embodiments, one or more alkanes are present in an amount from about 5% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 5% to about 25% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 7.5% to about 12.5% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 2.5% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, one or more alkanes are present in an amount from about 5% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, the one or more alkanes is about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5% of the total weight of the pharmaceutical composition. %, about 8%, about 8.5%, about 9%, about 9.5%, or about 10%. In some embodiments, the one or more alkanes is about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4% of the total weight of the pharmaceutical composition, Present in an amount of about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, or about 9%. In some embodiments, the pharmaceutical compositions described herein comprise from about 5% to about 15% by weight liquid paraffin.

[0082] In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizer, and at least one solubilizer comprises a fatty alcohol. In some embodiments, the fatty alcohol is a fatty alcohol of at least 9 carbons. In some embodiments, pharmaceutical compositions comprise one or more fatty alcohols. In some embodiments, the fatty alcohol is 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28 , 29, 30, 31, 32, 33, or 34 carbon alcohols. In some embodiments, fatty alcohols include alcohols with 12-24 carbons. In some embodiments, fatty alcohols include alcohols of 9-32, 8-24, 9-18, 12-24, or 15-24 carbons. In some embodiments, the fatty alcohol is fully saturated or partially saturated. In some embodiments, the fatty alcohol has a linear structure. In some embodiments, the fatty alcohol is branched. In some embodiments, the fatty alcohol is stearyl alcohol. In some embodiments, the fatty alcohol is present in an amount from about 0.1% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, the fatty alcohol (such as stearyl alcohol) is present in an amount from about 1% to about 10% of the total weight of the pharmaceutical composition. In some embodiments, the fatty alcohol is from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 6%, or from about 4% to about 10% by weight of the total pharmaceutical composition. It is present in amounts up to about 5%. In some embodiments, the fatty alcohol is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5% of the total weight of the pharmaceutical composition. %, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8%.

[0083] In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizer, and at least one solubilizer comprises a fatty acid. In some embodiments, the fatty acid is an at least 9 carbon fatty acid. In some embodiments, pharmaceutical compositions comprise one or more fatty acids. In some embodiments, the fatty acid is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, Contains 29, 30, 31, 32, 33, or 34 carbons. In some embodiments, fatty acids include 9-32, 8-24, 9-18, 12-24, or 15-24 carbon acids. In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent, wherein the at least one solubilizing agent is one or more each independently having at least 9 carbons. of partially saturated hydrocarbons. In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent, and the at least one solubilizing agent comprises a diol such as propyl glycol. In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent, wherein the at least one solubilizing agent comprises a polyol such as glycerin. In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizer, wherein the at least one solubilizer is one or more polyethoxylated glycerides, such as polyethoxylated monoglycerides, polyethoxylated diglycerides and/or polyethoxylated triglycerides (eg, polyethoxylated hydrogenated castor oil sold under the trade name Kolliphor® RH40). In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent, and at least one solubilizing agent comprises polyethylene glycol. In some embodiments, the polyethylene glycol has a weight average have a molecular weight. In some embodiments, polyethylene glycol has a weight average molecular weight of from about 3000 Da to about 4000 Da. In some embodiments, polyethylene glycol has a weight average molecular weight from about 2000 Da to about 6000 Da. In some embodiments, polyethylene glycol has a weight average molecular weight from about 2000 Da to about 8000 Da. In some embodiments, the polyethylene glycol is PEG3500. In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizing agent and at least one solubilizing agent comprises.

[0084] In some embodiments, the pharmaceutical compositions described herein comprise at least one solubilizer, wherein the at least one solubilizer comprises (i) about 20% of the total weight of the pharmaceutical composition. % to about 99.9% of petroleum jelly, (ii) liquid paraffin in an amount of about 0% to about 30% of the total weight of the pharmaceutical composition, and (iii) optionally, stearyl alcohol in an amount from about 0.1% to about 15% by total weight. In some embodiments, the pharmaceutical compositions described herein consist of an API (such as clofazimine) or a pharmaceutically acceptable salt thereof and at least one solubilizer, wherein the at least one solubilizer is (i) petroleum jelly in an amount from about 20% to about 99.9% by total weight of the pharmaceutical composition; and (ii) liquid paraffin in an amount from about 0% to about 30% by total weight of the pharmaceutical composition. including. In some embodiments, liquid paraffin is present in an amount from about 0.5% to about 30% of the total weight of the pharmaceutical composition.

[0085] Those skilled in the art will appreciate that other excipients or ingredients can be added or mixed with the solubilizer to enhance the properties or performance of the solubilizer or the resulting formulation. Examples of such excipients include, but are not limited to, surfactants, emulsifiers, thickeners, colorants, and the like.

[0086] In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

Penetration enhancer
[0087] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, and a penetration enhancer.

[0088] The stratum corneum is the outermost layer of the epidermis and consists of 15-20 layers of dead cells (keratinocytes) that do not contain a nucleus or organelles, embedded in a lipid matrix of ceramides, cholesterol, and fatty acids. Desquamation is the process of shedding cells from the surface of the stratum corneum; cells migrate through the epidermis toward the surface over a period of 14 days. The stratum corneum is 10-40 μm thick and acts as a barrier that protects the body's internal structures from external damage and protects the underlying tissues from infection, dehydration, chemicals, and mechanical stress. The cells of the stratum corneum contain a dense network of keratin that helps keep the skin moist by preventing water from evaporating. In addition, this layer is responsible for the "elasticity" or elasticity of the skin. Failure to maintain normal skin barrier function due to dysregulation of epidermal components may lead to skin disorders. The skin is an attractive target for drug administration (sometimes referred to as topical administration). It provides an easily accessible route with no first-pass metabolism and allows local drug delivery via the site of application with high patient compliance. However, successful transdermal drug delivery requires overcoming the poor permeability of the stratum corneum. One approach to overcome this problem is to use penetration enhancers.

[0089] Penetration enhancers are agents that partition into the stratum corneum and interact with components of the stratum corneum to temporarily and reversibly increase skin permeability. Penetration enhancers thus reversibly reduce the barrier properties of the stratum corneum to drug penetration and allow drugs to more readily penetrate living skin tissue and possibly into the systemic circulation. become. The advantages of chemical enhancers over physical enhancers (e.g., iontophoresis, sonophoresis, electroporation) are flexibility in design, ease of application, potential for self-administration, and long-term drug delivery via patches. , patient compliance, and incorporation into inexpensive and simple formulations. Table 4 provides a listing of various chemical classes and exemplary members of the class of penetration enhancers for use in the pharmaceutical compositions described herein. In some embodiments, the pharmaceutical compositions described herein comprise an API of Table 1 and a penetration enhancer of Table 4. In some embodiments, the pharmaceutical composition comprises (a) an API selected from Table 1, (b): (i) petroleum jelly, (ii) one each independently having at least 9 carbons or at least one solubilizing agent comprising one or more of a plurality of alkanes, (iii) fatty alcohols having at least 9 carbons, and (iv) fatty acids having at least 9 carbons, and optionally Contains penetration enhancers from Table 4.

[0090] In some embodiments, the penetration enhancer is a compound or mixture of compounds that includes a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group. They may serve one or more roles including penetration enhancers, solubility enhancers, bioavailability enhancers, stability enhancers, antioxidants and emulsifiers. Other terms in the art for penetration enhancer include emulsifiers, emulsifiers, surfactants, wetting agents, suspending agents and the like. Examples of penetration enhancers include phospholipids, sucrose fatty acid esters, polyoxylstearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan Monopalmitate, Sorbitan Monolaurate, Polysorbate, Glyceryl Monostearate, Sodium Lauryl Sulfate, Sodium Dodecyl Sulfate, Lauromacrogol Arlasolve, Poloxamer, Labrafil, Labrasol, Tween 80 and the like.

[0091] In some embodiments, the penetration enhancer is SDS, ethanol, DMSO, polyoxyethylene (80) sorbitan monooleate, polyoxyethylene (20) sorbitan monooleate, octanol, oleic acid or lecithin. be. In some embodiments, the penetration enhancer is octanol. In some embodiments, the penetration enhancer is lecithin. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, lipids are fatty acids and derivatives thereof that are insoluble in water and polar solvents, but soluble in non-polar or organic solvents. Categories of lipids include, but are not limited to, fatty acids, phospholipids, sphingolipids, glycolipids, polyketides, sterol lipids, prenol lipids, and the like. In some embodiments, the phospholipid is composed of glycerol and two fatty acids with attached phosphate groups. Other terms in the art for phospholipids include glycerophospholipids, phosphoglycerides, diacylglycerides, and the like. The phosphate group is either unmodified (i.e., R=H in the structures below) or modified by attachment to simple organic molecules such as, but not limited to, choline, ethanolamine, or serine. (ie, R≠H in the structure below). Phospholipids can be further modified by substitutions in one or more of the hydrocarbon chains.

[0093] In some embodiments, the phospholipids are selected from glycerophospholipids, sphingolipids, and/or phospholipid derivatives. In some embodiments, glycerophospholipids include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and mixtures thereof. Phospholipid derivatives according to the present disclosure include dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadeanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidonyiphosphatidylcholine ( DAPC), dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), and distearoylphosphatidylethanolamine (DSPE), distearoylphosphatidylglycerol (DSPG), phosphatidylinositol, dipalmitoylphosphatidylphosphatidic acid (DPPA), distearoyl phosphatidic acid (DSPA) and the like, and mixtures thereof, without limitation.

[0094] In some embodiments, a phosphatidylcholine is a phospholipid in which a choline group ( _Me3N ⁺ _-CH2 -CH2 _- O-) is attached to a phosphate group.

A non-limiting example of phosphatidylcholine is 1-oleoyl-2-palmitoyl-phosphatidylcholine, as shown below.

[0095] In some embodiments, the lecithin is a mixture of phospholipids. Lecithin can be isolated from a variety of sources including, but not limited to, eggs, soybeans, milk, marine sources, rapeseed, cottonseed, and sunflower.
[0096] In some embodiments, the penetration enhancer is a phospholipid. In some embodiments, the phospholipid is phosphatidylcholine. In some embodiments, the phospholipid is a mixture comprising phosphatidylcholine. In some embodiments, the penetration enhancer is lecithin. In some embodiments, the phosphatidylcholine is lecithin. In some embodiments, lecithin contains greater than 25% phosphatidylcholine. In some embodiments, lecithin contains greater than 80% phosphatidylcholine. In some embodiments, the phosphatidylcholine is egg-derived. In some embodiments, the phosphatidylcholine is soy-derived. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0097] In one aspect, the pharmaceutical compositions described herein comprise an API (such as clofazimine) or a pharmaceutically acceptable salt thereof, at least one solubilizer, and a stratum corneum penetration enhancer. In some embodiments, the stratum corneum penetration enhancer is polyethoxylated sorbitan monooleate, laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or combinations thereof. In some embodiments, the stratum corneum penetration enhancer is selected from Table 4. In some embodiments, the stratum corneum penetration enhancer is lecithin. In some embodiments, the stratum corneum penetration enhancer is present in an amount from about 1% to about 20% of the total weight of the pharmaceutical composition.

[0098] In some embodiments, the penetration enhancer comprises from about 1% to about 20% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the penetration enhancer is about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 2% to about 12%, or about 7.5% to about 12.5%. configure. In some embodiments, penetration enhancers constitute about 1% of the total weight of the pharmaceutical compositions described herein. In some embodiments, the penetration enhancer constitutes about 1% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 2% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 3% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 4% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 5% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 6% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 7% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 8% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 9% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 10% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 11% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 12% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 13% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 14% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 15% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 16% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 17% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 18% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 19% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 20% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 25% of the total weight of the composition. In some embodiments, the penetration enhancer constitutes about 30% of the total weight of the composition. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the pharmaceutical composition comprises a lipophilic API, a solubilizer, and a penetration enhancer. In some embodiments, the weight ratio of API to (solubilizer+penetration enhancer) is from about 1:25 to 1:2500. In some embodiments, the weight ratio of API to (solubilizer+penetration enhancer) is from about 1:50 to 1:2000. In some embodiments, the weight ratio of API to (solubilizer+penetration enhancer) is from about 1:100 to 1:1000. In some embodiments, the weight ratio of API to (solubilizer+penetration enhancer) is from about 1:100 to 1:500. In some embodiments, the weight ratio of API to (solubilizer+penetration enhancer) is about 1:250. In some embodiments, the weight ratio of penetration enhancer to solubilizer is from about 1:1 to 1:50. In some embodiments, the weight ratio of penetration enhancer to solubilizer is from about 1:2 to 1:20. In some embodiments, the weight ratio of penetration enhancer to solubilizer is from about 1:2 to 1:10. In some embodiments, the weight ratio of penetration enhancer to solubilizer is from about 1:3 to 1:5. In some embodiments, the weight ratio of penetration enhancer to solubilizer is about 1:4. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is one listed in Table 1, or a pharmaceutically acceptable salt thereof.
gelling agent
[00100] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API (eg, clofazimine), at least one solubilizer, and optionally a penetration enhancer. In some embodiments, pharmaceutical compositions may optionally include one or more gelling agents.

[00101] Gels are transparent or translucent, semisolid, highly crosslinked polymeric matrices. They contain a small amount of solid gelling agent dispersed in a relatively large amount of liquid; most of their contents are liquid, but exhibit more solid-like properties. When dispersed in a suitable solvent, the gelling agents coalesce or entangle to form a three-dimensional network that restricts fluid flow by trapping and immobilizing solvent molecules. A gel is formed when particles of the gelling agent are crosslinked by chemical bonding or physical interactions (eg, hydrogen bonding) into a three-dimensional network that behaves almost like a liquid but a solid.

[00102] Creams, ointments, gels, pastes and the like have been used as topical dosage forms. Topical gel formulations can offer the following advantages as drug delivery systems: less greasy than creams or ointments; possess better application properties; excess gel is easily removed from the skin; Usually more stable than creams and ointments.

[00103] Various types of gels exist, including but not limited to:
Hydrogels - consist of high water content and are super absorbent.
Organogel - Amorphous, non-glassy thermoplastic solid material composed of a liquid organic phase entrapped in a three-dimensionally crosslinked network.
Xerogel - A solid formed from a gel that does not shrink in the process and generally retains a high degree of porosity. Examples include rubber and gelatin.
Airgel - A low density material produced when the liquid component of a gel is replaced by a gas (eg nitrogen, air).
Others include inorganic, organic, biopolymers, monomer gels, emulgels, in situ gels, microemulsion gels, and the like.

[00104] Polyacrylic acid (PAA or carbomer or carbopol) is a synthetic high molecular weight polymer of acrylic acid. Its chemical name is poly(1-carboxyethylene).

[00105] Carbomer is water soluble, can absorb and retain water, can swell up to 1000 times its initial volume, and can therefore be used as a gelling agent. Carbomers are often accompanied by a code (eg, such as 940, 934, 940, 941, 934P, etc.) that reflects the molecular weight and composition of the polymer.

[00106] In aqueous solutions at neutral pH, carbomers are anionic polymers, ie, many of the acid side chains lose their protons and acquire a negative charge. Carbomers can be used as alkali metal or ammonium salts, such as sodium polyacrylate. In dry powder form, positively charged sodium ions are bound to the polyacrylate. In aqueous solution, sodium ions are free to move as they are displaced by positively charged hydrogen ions. Instead of organized polymer chains, this leads to swollen gels that can absorb high volumes of water.

[00107] Gelation may be performed in a two-step process. First, the carbomer is hydrated and dispersed throughout the aqueous medium. The solution is then neutralized by the addition of base. Neutralizing agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide or organic amines such as triethanolamine (TEA). About 0.01 equivalents of base are required to neutralize 1 g of carbomer to pH 7.

[00108] In some embodiments, the pharmaceutical compositions described herein are gels. In some embodiments, pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, a penetration enhancer and a gelling agent.

[00109] In some embodiments, the gelling agent is carbomer, polyacrylic acid, hyaluronic acid, polyvinyl alcohol, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), sodium CMC, hypromellose, carbopol, polyvinyl alcohol, polyvinyl methacrylic acid, polaxamer, adenosylcobalamin, gellan gum, pectin, high methoxyl pectin (HMP), low methoxyl pectin (LMP), tragacanth, acacia, or a combination of these.

[00110] In some embodiments, the gelling agent is carbomer, polyacrylic acid, polyvinyl alcohol, cellulose, methylcellulose, ethylcellulose, hypromellose, hydroxyethylcellulose, hyaluronic acid, or combinations thereof. In some embodiments, the gelling agent is carbomer. In some embodiments, the gelling agent is Carbomer 940. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00111] In some embodiments, the gelling agent comprises about 0.1% to 5% of the total weight of the composition. In some embodiments, the gelling agent is about 0.1% to about 0.5%, about 0.1% to about 1%, about 0.2% to about 1%, about constitute 0.5% to about 2.5%, about 0.5% to about 5%, about 1% to about 2%, about 1% to about 5%, or about 0.5% to about 3% . In some embodiments, the gelling agent constitutes about 0.1% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.2% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.3% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.4% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.5% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.6% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.7% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.75% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.8% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 0.9% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.0% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.2% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.3% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.4% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.5% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.6% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.7% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.8% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 1.9% of the total weight of the composition. In some embodiments, the gelling agent constitutes about 2.0% of the total weight of the composition. In some embodiments, the gelling agent constitutes less than 2.0% of the total weight of the composition. In some embodiments, the gelling agent constitutes less than 1.5% of the total weight of the composition. In some embodiments, the gelling agent constitutes less than 1% of the total weight of the composition. In some embodiments, the gelling agent constitutes less than 0.75% of the total weight of the composition. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00112] In some embodiments, the weight ratio of gelling agent to (API + solubilizing agent + penetration enhancer) is about 1:5. In some embodiments, the weight ratio of gelling agent to (API + solubilizing agent + penetration enhancer) is about 1:10. In some embodiments, the weight ratio of gelling agent to (API + solubilizing agent + penetration enhancer) is about 1:50. In some embodiments, the weight ratio of gelling agent to (API + solubilizing agent + penetration enhancer) is about 1:250. In some embodiments, the weight ratio of gelling agent to (API + solubilizing agent + penetration enhancer) is about 1:500. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

Neutralizing agent
[00113] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, at least one solubilizer and optionally a penetration enhancer. In some embodiments, the pH of the pharmaceutical composition is 9.5 or less. In some embodiments, the pH is 9.0 or less. In some embodiments, the pH is 8.5 or less. In some embodiments, the pH is 8.0 or less. In some embodiments, the pH is 7.5 or less. In some embodiments, the pH is about 6-8. In some embodiments, the pH is about 6-7. In some embodiments, the pH is about 5-7. In some embodiments, the pH is about 5-6. In some embodiments, the pH is about 4-9. In some embodiments, the pH is about 6.5-7.5. In some embodiments, the pH is below 4 or 5. In some embodiments, the pH is higher than 6, 7, 8, or 9. In some embodiments, the pH is about 7. In some embodiments, the pH of the pharmaceutical composition is adjusted to the desired pH by the addition of neutralizing agents (or pH adjusters). In some embodiments, the neutralizing agent is triethanolamine, ethylenediamine, sodium citrate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium hydrogen phosphate, or combinations thereof. In some embodiments, the neutralizing agent is triethanolamine. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein comprise lipophilic APIs, solubilizers, penetration enhancers, gelling agents and neutralizing agents.
water
[00114] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, optionally a penetration enhancer, and optionally water. In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, a solubilizer, optionally a penetration enhancer, optionally a gelling agent, optionally a neutralizing agent and optionally a neutralizing agent. contains water. In some embodiments, the pharmaceutical composition comprises about 30% to about 95% water. In some embodiments, the pharmaceutical composition comprises about 40% to about 90% water by weight. In some embodiments, the pharmaceutical composition comprises about 50% to about 90% water by weight. In some embodiments, the pharmaceutical composition comprises about 60% to about 80% water by weight. In some embodiments, the pharmaceutical composition comprises about 70% to about 80% water by weight. In some embodiments, the pharmaceutical composition comprises about 75% to about 80% water by weight. In some embodiments, the pharmaceutical composition comprises about 75% water by weight. In some embodiments, the pharmaceutical composition comprises less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% water by weight. In some embodiments, the pharmaceutical composition does not contain water. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein are water free.

Other additives
[00115] In some embodiments, the pharmaceutical compositions described herein comprise a lipophilic API, at least one solubilizer, optionally a penetration enhancer, and optionally one or more Contains additives. In some embodiments, the pharmaceutical compositions described herein comprise a fat-soluble API, a solubilizer, a penetration enhancer, a gelling agent, a neutralizing agent, optionally water and, optionally, 1 Contains one or more additives. In some embodiments, the pharmaceutical composition further comprises a moisturizer. In some embodiments, the humectant is glycerin, urea, allantoin, or a combination thereof. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00116] In some embodiments, the pharmaceutical compositions described herein further comprise a preservative. In some embodiments, the preservative is sodium benzoate, chlorobutanol, paraben or sorbic acid. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00117] The compositions described herein may optionally contain an antioxidant. In some embodiments, antioxidants are used to reduce oxidation or degradation of APIs and excipients in the composition. In some embodiments, the antioxidants are ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, cysteine, gallic acid, guaiac butter, methionine, phosphoric acid, meta Potassium bisulfite, propyl gallate, sesamol, sodium edate, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, terbuterylhydroquinone, tartaric acid, tertiary butylhydroquinone, vitamin E (tocopherol), thioglycerol, thio selected from glycolic acid, or combinations thereof. In some embodiments, the antioxidant is vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, or combinations thereof. In some embodiments, the antioxidant is vitamin E, 2,6-di-tert-butyl-4-methylphenol, butylhydroxyanisole, ascorbyl palmitate, tert-butylhydroquinone, or combinations thereof.

[00118] In some embodiments, one or more excipients are present in an amount less than 2.0% of the total weight of the pharmaceutical compositions described herein. In some embodiments, one or more additives are present in an amount less than 1.75% of the total weight of the composition. In some embodiments, one or more additives are present in an amount less than 1.5% of the total weight of the composition. In some embodiments, one or more additives are present in an amount less than 1.25% of the total weight of the composition. In some embodiments, one or more additives are present in an amount less than 1.0% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.1% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.2% of the total weight of the composition. In some embodiments, the pharmaceutical compositions described herein comprise a fat-soluble API, long chain fatty acids or long chain fatty acid glycerides, phospholipids and, optionally, one or more excipients. In some embodiments, one or more additives constitute about 0.3% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.4% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.5% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.6% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.7% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.8% of the total weight of the composition. In some embodiments, one or more additives constitute about 0.9% of the total weight of the composition. In some embodiments, one or more additives constitute about 1.0% of the total weight of the composition. In some embodiments, one or more additives constitute about 1.1% of the total weight of the composition. In some embodiments, one or more additives constitute about 1.2% of the total weight of the composition. In some embodiments, one or more additives constitute about 1.25% of the total weight of the composition. In some embodiments, one or more additives are present in an amount from about 0.01% to about 2% of the total weight of the composition. In some embodiments, one or more additives are present in an amount from about 0.1% to about 1.75% of the total weight of the composition. In some embodiments, one or more additives are present in an amount from about 0.2% to about 1.5% of the total weight of the composition. In some embodiments, one or more additives are present in an amount from about 0.3% to about 1.25% of the total weight of the composition. In some embodiments, one or more additives are present in an amount from about 0.4% to about 1.1% of the total weight of the composition.

[00119] In some embodiments, other additives conventionally used in pharmaceutical compositions may be included, and these additives are well known in the art. Such additives include, but are not limited to, anti-adherents (anti-sticking agents, lubricants, glidants, lubricants) such as talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica ( Syloid No. FP 244, Grace U.S.A.), polyethylene glycol, surfactant, wax, stearic acid, stearate, stearic acid derivative, starch, hydrogenated vegetable oil, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate) anticoagulants (e.g. acetylated monoglycerides), antifoam agents (e.g. long chain alcohols and silicone derivatives), antioxidants (e.g. BHT, BHA, gallic acid, gallic acid) propyl, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butylphenol, tocopherol, etc.), binders (adhesives), i.e. imparting cohesiveness to powdered materials through particle-particle bonding agents (e.g. matrix binders (dry starch, dry sugar), film binders (PVP, starch paste, cellulose, bentonite, sucrose)), chemical binders (e.g. polymeric cellulose derivatives such as carboxymethylcellulose, HPC, HPMC etc., sugar syrup, corn syrup, water-soluble polysaccharides (e.g. acacia, tragacanth, guar, alginate, etc.), gelatin, gelatin hydrolysates, agar, sucrose, dextrose, non-cellulose binders (e.g. PVP, PEG, vinylpyrrolidone). copolymers, pregelatinized starch, sorbitol, glucose, etc.), buffers (acids containing pharmaceutically acceptable acids (e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, boric, phosphoric Acids, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid ), isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid , toluenesulfonic acid, uric acid, etc.), and the base is a pharmaceutically acceptable base (e.g., amino acid, amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate , magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or acetic acid, acrylic acid, adipine Acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methane Pharmaceutically acceptable sulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid chelating agents (e.g. EDTA and EDTA salts), coagulants (e.g. alginates) coloring or opacifying agents (e.g. titanium dioxide, food coloring, lakes, natural vegetable colorings, oxidation iron, silicates, sulfates, magnesium hydroxide and aluminum hydroxide), coolants (e.g. halogenated hydrocarbons (e.g. trichloroethane, trichlorethylene, dichloromethane, fluorotrichloromethane), diethyl ether and liquid nitrogen), cryoprotectants ( trehalose, phosphate, citric acid, tartaric acid, gelatin, dextran, mannitol, etc.), diluents or fillers such as lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride , citric acid, spray-dried lactose, hydrolyzed starch, directly compressible starch, microcrystalline cellulose, cellulose derivatives, sorbitol, sucrose, sucrose-based substances, calcium sulfate, dicalcium phosphate and dextrose disintegrants or superdisintegrants ( super disintegrant) (e.g. croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivatives, alginates, crosslinked polyvinylpyrrolidone, sodium starch glycolate and microcrystalline cellulose), hydrogen bonding agents (e.g. oxidation magnesium), flavors or desensitizing agents (e.g. spray dried flavors, essential oils and ethyl vanillin), ion exchange resins (e.g. styrene/divinylbenzene copolymers, and quaternary ammonium compounds), plasticizers (e.g. polyethylene glycol, Citrate esters (e.g. triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalates (e.g. diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate), preservatives (e.g. ascorbic acid), boric acid, sorbic acid, benzoic acid and their salts, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds), solvents (e.g. alcohols, ketones, esters, chlorinated hydrocarbons and water) sweeteners such as natural sweeteners (e.g. maltose, sucrose, glucose, sorbitol, glycerin and dextrins) and artificial sweeteners (e.g. aspartame, saccharin and saccharin salts) and thickeners (viscosity modifiers, thickeners) such as sugars, polyvinylpyrrolidone, cellulose derivatives, polymers and alginates.

[00120] Additives also include proteins (e.g., collagen, gelatin, zein, gluten, mussel proteins, lipoproteins), carbohydrates (e.g., alginates, carrageenans, cellulose derivatives, pectin, starch, chitosan), gums (e.g., xanthan gum, gum arabic), spermaceti, natural or synthetic waxes, carnauba wax, fatty acids (e.g. stearic acid, hydroxystearic acid), fatty alcohols, sugar, shellac, e.g. sugar-based (e.g. lactose) , sucrose, dextrose) or starch, polysaccharide-based polymers (e.g. maltodextrin and maltodextrin derivatives, dextrates, cyclodextrins and cyclodextrin derivatives), cellulose-based polymers (e.g. microcrystalline cellulose, carboxy sodium methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate, trimellitate, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate), inorganic compounds such as dicalcium phosphate, hydroxyapatite, tricalcium phosphate, talc and titania), polyols (e.g. mannitol, xylitol and sorbitol polyethylene glycol esters) and polymers (e.g. alginates, poly(lactide-co-glycolide), gelatin, cross-linked gelatin and agar - agar).

[00121] A given ingredient is often categorized differently by the actual practitioner, or is typically used for any of several different functions, or varies depending on its level in the composition. It will be appreciated that there is generally considerable overlap between the components in the above list as they may have functions. Accordingly, the above list of ingredients is merely representative, and not limiting, of the types of ingredients that can be included in the compositions of the present disclosure.

[00122] Other agents suitable for inclusion in the pharmaceutical compositions include humectants such as propylene glycol, glycerin, butylene glycol, sorbitol, triacetin, and mixtures thereof; fragrances such as lavender oil, rose oil, lemon oil, almond oil, other FDA approved fragrances, and mixtures thereof; cooling agents such as menthol, such as l-menthol and dl-menthol; camphor, such as d-camphor and dl-camphor; borneol, Examples include d-borneol and dl-borneol; and mixtures thereof.

stabilizer
[00123] In some embodiments, the compositions disclosed herein comprise a stabilizer. In some embodiments, either solubilizers, penetration enhancers, gelling agents, or additives serve additional functions of stabilizers. In some embodiments, the stabilizer reduces degradation of the active pharmaceutical ingredient, eg, API of Table 1, in the composition.

[00124] In some embodiments, the compositions disclosed herein comprise clofazimine. Clofazimine is oxidatively and hydrolytically degraded and requires stabilization for storage. In some embodiments, the stabilizer is selected from labrasol, Transcutol, propyl glycol, oleic acid, glycerin, PEG 3350, Polyoxyl 40 hydrogenated castor oil (RH 40), stearyl alcohol, petrolatum, and liquid paraffin. In some embodiments, the stabilizer is selected from propyl glycol, glycerin, PEG 3350, Polyoxyl 40 hydrogenated castor oil (RH 40), stearyl alcohol, petrolatum, and liquid paraffin. In some embodiments, stabilizers are selected from stearyl alcohol, petrolatum, and liquid paraffin.

Stability
[00125] The topical formulations described herein are chemically and physically stable for extended periods of time under a variety of storage conditions. The term "stable," as used herein, can mean a formulation that maintains its appearance (eg, color, uniformity, no aggregation) after a given period of storage. The term "stable" as used herein also refers to the API content after a given storage period, e.g. It can also mean a formulation that maintains %. Also, the term "stable" as used herein means no more than 2% w/w of total impurities or less than 1% w/w of single can also mean formulations that retain impurities of The term "stable," as used herein, can also mean formulations that retain microbial levels below a specified limit after a given storage period. In some embodiments, the period or storage period is at least 7 days, at least 14 days, at least 15 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, formulations described herein are stable for at least 6 months. In some embodiments, formulations described herein are stable for at least 12 months. In some embodiments, formulations described herein are stable for at least 18 months. In some embodiments, formulations described herein are stable for at least 24 months. In some embodiments, the storage condition is a refrigeration temperature, such as about 4°C. In some embodiments, the storage condition is about 40°C. In some embodiments, storage conditions are about 25°C. In some embodiments, the storage conditions are accelerated conditions of about 40° C. and about 75% RH. In some embodiments, storage conditions are about 25° C. and about 60% RH.

[00126] In some embodiments, the formulations described herein have an assay value of 90% or more and 110% or less of the labeled amount of the API (eg, clofazimine or the API of Table 1). In some embodiments, assay values can be measured using HPLC methods. In some embodiments, the formulations described herein are about 85% to about 115%, about 90% to about 110%, about 95% after a given storage period of labeled API (eg, clofazimine) % to about 105%, about 98% to about 102%, or 99% to about 101%. In some embodiments, formulations described herein exhibit an assay value of from about 90% to about 110% after a given storage period of labeled API (e.g., clofazimine) when stored at 40°C. have. In some embodiments, formulations described herein have an assay value of from about 90% to about 110% after a given storage period of labeled API when stored at 25°C. In some embodiments, the API in the stable formulations described herein is at least about 85% w/w, at least about 86% w/w, at least about 87% w/w after a given storage period , at least about 88% w/w, at least about 89% w/w, at least about 90% w/w, at least about 91% w/w, at least about 92% w/w, at least about 93% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 98% w/w, at least about 99% w/w, or at least about It has an initial API content of 100% w/w. In some embodiments, formulations described herein retain from about 90% to about 110% w/w of the initial amount of API after a given period of storage. In some embodiments, formulations described herein retain from about 95% to about 105% w/w of the initial amount of API after a given period of storage. In some embodiments, the formulations described herein contain at least about 85% w/w, at least about 86% w/w, at least about 87% w/w of the initial amount of API after a given shelf life, at least about 88% w/w, at least about 89% w/w, at least about 90% w/w, at least about 91% w/w, at least about 92% w/w, at least about 93% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 98% w/w, at least about 99% w/w, or at least about 100 Retain %w/w. In some embodiments, the API in the stable formulations described herein is up to about 115% w/w, up to about 110% w/w, up to about 110% w/w, up to about 109% w/w, up to about 108% w/w, up to about 107% w/w, up to about 106% w/w, up to about 105% w/w, up to about 104% w /w, up to about 103% w/w, up to about 102% w/w, up to about 101% w/w, or up to about 100% w/w. In some embodiments, the API in the stable formulations described herein is about 100±15% w/w, about 100±10% w/w of the initial amount of API after a given storage period, about 100±9% w/w, about 100±8% w/w, about 100±7% w/w, about 100±6% w/w, about 100±5% w/w, about 100±4% w /w, about 100±3% w/w, about 100±2.5% w/w, about 100±2.0% w/w, about 100±1.5% w/w, about 100±1. 0% w/w, or within the range of about 100±0.5% w/w. In some embodiments, formulations described herein have an assay value of from about 90% to about 110% of the initial API amount after a given storage period when stored at 25°C. In some embodiments, formulations described herein have an assay value of about 90% to about 110% of the initial API amount after a given storage period when stored at 40°C. In some embodiments, the formulations described herein have an assay value of about 95% to about 105% of the initial API amount after a given storage period when stored at 25°C and/or 40°C. . In some embodiments, formulations described herein have an assay value of from about 98% to about 102% of the initial API content after a given storage period when stored at 25°C and/or 40°C . In some embodiments, the amount of API is determined by liquid chromatography, such as high performance liquid chromatography (HPLC). In some embodiments, the total impurities in the stable formulations described herein are about 0.1% w/w, about 0.2% w/w based on the weight of the initial amount of API after a given storage period. % w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2.0% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w , or about 2.5% w/w or less. In some embodiments, the total impurities in the stable formulations described herein are about 0.5% w/w, about 1.0% w/w based on the weight of the formulation after a given storage period. w, about 1.5% w/w, about 2.0% w/w, about 2.5% w/w, about 3.0% w/w, about 3.5% w/w, about 4. 0% w/w, about 4.5% w/w, about 5.0% w/w, or about 10% w/w or less. In some embodiments, the storage period is at least 6 months, at least 9 months, at least 12 months, or any period in between. In some embodiments, the shelf life is at least 6 months. In some embodiments, the storage period is at least 9 months. In some embodiments, storage conditions have a relative humidity of about 60%. In some embodiments, storage conditions have a relative humidity of about 75%. In some embodiments, storage conditions have a temperature of about 40°C. In some embodiments, storage conditions have a temperature of about 25°C. In some embodiments, the API is clofazimine. In some embodiments, the API is the API of Table 1.

[00127] In some embodiments, the compositions disclosed herein comprise clofazimine and at least one stabilizer. In some embodiments, the composition is stable for 3 days at 60°C. In some embodiments, the composition is stable for 1, 2, 3, 4, 5, 6, 7, 8, 9, or more months at room temperature and various humidity levels (e.g., 60% and 75%). be. In some embodiments, the composition is stable at elevated temperature and humidity (eg, 75%) for 1, 2, 3, 4, 5, 6, 7, 8, 9, or more months. In some embodiments, the amount of total impurities resulting from degradation is about 0.01%, 0.05%, 0.1%, based on the weight of the initial amount of API or the weight of the formulation after a given storage period, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0% or 5.0% or less. In some embodiments, the amount of impurities resulting from decomposition is from about 0.01% to about 5%. In some embodiments, the amount of impurities resulting from degradation is from about 0.01% to about 0.05%, about 0.01% based on the weight of the initial API amount or weight of the formulation after a given storage period. to about 0.1%, about 0.01% to about 0.25%, about 0.01% to about 0.5%, about 0.01% to about 0.75%, about 0.01% to about 1%, about 0.01% to about 2%, about 0.01% to about 3%, about 0.01% to about 5%, about 0.1% to about 0.25%, about 0.1% from about 0.5%, from about 0.1% to about 0.75%, from about 0.1% to about 1%, from about 0.1% to about 2%, from about 0.1% to about 3%, or About 0.1% to about 5%. In some embodiments, the amount of total impurities resulting from decomposition is less than about 0.2% based on the weight of the initial API amount over 9 months. In some embodiments, the amount of total impurities resulting from decomposition is less than about 0.15% over 9 months. In some embodiments, the amount of total impurities resulting from degradation is about 2% or less based on the weight of the initial amount of API after a given storage period. In some embodiments, the amount of total impurities resulting from degradation is about 1% or less based on the weight of the initial amount of API after a given storage period. In some embodiments, the amount of a single impurity as a result of degradation is about 1% or less based on the weight of the initial amount of API after a given storage period. In some embodiments, the amount of a single impurity as a result of degradation is about 0.5% or less based on the weight of the initial amount of API after a given storage period. In some embodiments, total impurities are determined by liquid chromatography, such as high performance liquid chromatography (HPLC). In some embodiments, the storage period is at least 6 months, at least 9 months, at least 12 months, or any period in between. In some embodiments, the shelf life is at least 6 months. In some embodiments, the storage period is at least 9 months. In some embodiments, storage conditions have a relative humidity of about 60%. In some embodiments, storage conditions have a relative humidity of about 75%. In some embodiments, storage conditions have a temperature of about 40°C. In some embodiments, storage conditions have a temperature of about 25°C. In some embodiments, the API is clofazimine. In some embodiments, the API is the API of Table 1.

[00128] In some embodiments, the formulations described herein are physically stable over a period of storage. In some embodiments, the API of the formulation remains dissolved without visually observed crystal formation over a storage period of at least 1, 6, 9, 12, or 12 months. In some embodiments, the API of the formulation remains dissolved without crystal formation observed by polarized light microscopy over a storage period of at least 1, 6, 9, 12, or 12 months. In some embodiments, the shelf life is at least 6 months. In some embodiments, the storage period is at least 9 months. In some embodiments, storage conditions have a temperature of about 40°C. In some embodiments, storage conditions have a temperature of about 25°C. In some embodiments, the API is clofazimine. In some embodiments, the API is the API of Table 1.

Method of administration
[00129] In some embodiments, the pharmaceutical compositions described herein are for topical administration. In some embodiments, pharmaceutical compositions described herein are for transdermal administration. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof. Accordingly, described herein are methods of treating a disease or condition in a subject in need thereof, comprising applying to the subject the topical formulations described herein. Further, according to the present invention, administration of the topical formulations described herein provides an API described herein (e.g., clofazimine or a pharmaceutically acceptable salt thereof) to the skin of a subject, e.g., the skin. Methods of delivery to the epidermal and/or dermal layers are provided.

[00130] Topical or transdermal administration refers to delivery of the API by passage and penetration through the skin or mucosal tissue. Accordingly, the terms "transdermal" and "transmucosal" are used synonymously unless otherwise indicated. Similarly, the terms "skin", "dermis", "epidermis", "mucosa" and the like are used synonymously unless otherwise indicated. Topical pharmaceutical compositions are applied to a specific location on or within the body. Most often, topical administration refers to applicability to bodily surfaces such as skin or mucous membranes. Topical administration may be directed to the skin surface, meaning that it is applied directly to the skin. In some cases, the formulation may be applied directly to the skin in a free form sufficient to effect transdermal delivery of the API without the use of structures such as backing members and the like. In some cases, the formulation may be applied to the skin with the aid of a structure such as a backing member, bandage or covering, eg a matrix patch.

[00131] There are several types of topical pharmaceutical compositions. In some embodiments, the pharmaceutical compositions described herein are gels, lotions, creams, ointments, topical solutions, drops, jellies, balms, foams, mousses, patches, pastes, aerosols. , sprays, powders, dispersible powders, granules, emulsions, sponges, tapes, tinctures or solids.

[00132] In some embodiments, the pharmaceutical composition is a gel, cream or ointment. In some embodiments the pharmaceutical composition is a gel. In some embodiments the pharmaceutical composition is a cream. In some embodiments, the pharmaceutical composition is an ointment. In some embodiments, the API is clofazimine, or a pharmaceutically acceptable salt thereof. In some embodiments, the API is listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00133] In some embodiments, the area to which the pharmaceutical composition is applied is washed prior to administration. In some embodiments, the area to which the pharmaceutical composition is applied is washed and dried prior to administration. In some embodiments, the area to which the pharmaceutical composition is applied is washed, dried and exfoliated prior to administration.

[00134] In some embodiments, the pharmaceutical compositions described herein are administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered three times daily. In some embodiments, the pharmaceutical composition is administered four times daily. In some embodiments, the pharmaceutical composition is administered more than four times daily. In some embodiments, the pharmaceutical composition is administered no more than once a day. In some embodiments, the pharmaceutical composition is administered at least once daily. In some embodiments, the pharmaceutical composition is administered at least twice daily. In some embodiments, the pharmaceutical composition is administered one or more times daily, at least 1 day, 3 days, 7 days, 14 days, 21 days, 28 days, January, February, March, June, December. , 2 years, or any number or range in between, e.g. , 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months be done. In some embodiments, the pharmaceutical composition is administered for at least one week, at least one month, at least three months, at least six months, or at least one year. In some embodiments, the pharmaceutical composition is administered for up to 1 month, up to 3 months, up to 6 months, up to 1 year, or up to 10 years. In some embodiments, the number of daily applications of the pharmaceutical composition depends on the severity of the disease or disorder being treated. In some embodiments, the pharmaceutical composition is administered as needed, ie, to alleviate symptoms of the disease or disorder.

[00135] In some embodiments, after administration of the composition to a topical area, the composition and area may be covered with a protective cloth, bandage, gauze, wrap, or the like. A protective cloth, bandage, gauze, or wrap can prevent transfer of the composition, for example, onto clothing, furniture, bedding, third parties, and the like. A protective cloth, bandage, gauze or wrap can protect the area from, for example, dust, pathogenic bacteria, and the like.

combination
[00136] In some embodiments, the pharmaceutical compositions described herein can further comprise a second API. In some embodiments, the second API is an anti-inflammatory agent, local anesthetic, or combination thereof. Typical local anesthetics include, but are not limited to lidocaine, xylocaine, buprenorphine and fentanyl. Suitable topical corticosteroids can be used as anti-inflammatory agents. Representative suitable corticosteroids include cortisol (hydrocortisone); tetrahydrocortisol; prednisone (cortisone); prednisolone (cortisol); 6α-methylprednisolone; fludrocortisone (9α-fluorocortisol); (11-dehydrocortisol); corticosterone; triamcinolone (9α-fluoro-16α-hydroxyprednisolone); paramethasone (6α-fluoro-16α-methylprednisolone); betamethasone (9α-fluoro-16β-methylprednisolone); -fluoro-16α-methylprednisolone); desoxycorticosterone acetate (doca acetate, percorten acetate); desoxycorticosterone pivalate (percorten pivalate); fludrocortisone acetate (florine acetate); cortef acetate, hydrocortone); cortisol cypionate (cortef); cortisol sodium phosphate (hydrocortone phosphate); cortisol sodium succinate (solu-cortef); beclomethasone dipropionate ( betamethasone sodium phosphate and acetate (celestone soluspan); betamethasone dipropionate (diprosone); betamethasone valerate (valisone); betamethasone benzoate (benisone, flurodate); cortone acetate); dexamethasone (decadron, gammacorten); dexamethasone sodium phosphate (decadron phosphate, hexadrol phosphate); dexamethasone acetate (decadron-LA); meprednisone (betapar); methylprednisolone (medrol ); methylprednisolone acetate (depo-medrol, medrol acetate); methylprednisolone sodium succinate (solu-medrol); paramethasone acetate (haldrone); prednisolone (delta-cortef); salt (hydeltrasol); prednisolone sodium succinate (meticortelone soluble); prednisolone tebutate (hydelta-T. B. A. triamcinolone (aristoderm, kenalog); triamcinolone diacetate (aristocort diacetate, kinacort diacetate); triamcinolone hexacoton ide (aristospan); desonide (tridesilon); desoxymeta flumethasone pivalate (locorten); fluocinolone acetonide (fluonid, synalar); fluocinonide (lidex, topsyn); fluorometholone (oxylone); Medrysone (HMS liquifilm, medrocort).

[00137] In some embodiments, the second API is an antipruritic. Antipruritic agents include, but are not limited to, pramoxine, diphenhydramine, benzocaine, lidocaine, bupivacaine, chloroprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, lignocaine, phenacaine, procaine, ketamine, phenol, butamben, butambenpicrate , cocaine, dimethisoquine, diperodone, dyclonine, methapyriline, oxyprocaine, p-butylaminobenzoic acid 2-(die-ethylamino) ethyl ester, piperocaine, prilocaine, tripelennamine, dyclonine, resorcinol, syncocaine, dexivacaine , diamocaine, levobupivacaine, oxethazaine, proparacaine, propoxycaine, pilocaine, risocaine, lodocaine, ropivacaine, pramocaine, proxazocaine, 4-(3-(p-butoxyphenoxy)propyl)morpholine, gamma-morpholinopropyl 4-n-butoxyphenyl ether, p-butoxyphenyl gamma-morpholinopropyl ether, 4-[3-(4-butoxyphenoxy)-propyl]morpholine, menthol, camphor, menthyl anthranilate, and pharmaceutically acceptable salts, derivatives thereof, and Mixtures of these are included.

[00138] In some embodiments, the second API is an antimicrobial agent. Examples of antibacterial agents include penicillins and related drugs, carbapenems, cephalosporins and related drugs, erythromycin, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, sodium fusidate, lincomycin, clindamycin, macrolides, novobiocin, polymyxin, rifamycin, spectinomycin, tetracycline, vanomycin, teicoplanin, streptogramin, antifolates such as sulfonamides, trimethoprim and combinations thereof and pyrimethamine, synthetic antimicrobials such as nitrofuran, mandel methenamine acid and methenamine hippurate, nitroimidazole, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone, biomycin, ebeminomycin, Glycopeptides, glyclyclines, ketolides, oxazolidinones; imipenem, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, Ziracin, linezolid, synercid, aztreonam, and metronidazole, Epiroprim, sunfethrinem sodium, biapenem, dinemicin, cefluplenam, cefoselis , Sanfetrinem cilexetil, cefpirome, mersacidin, rifalazil, Kosan, lenapenem, Veneprim, sulopenem, ritipenam acoxyl, cyclothialidine, micacocidin A, carmonam, cefozopran and cefetamethpivoxil.

[00139] In some embodiments, the second API is an anti-acne agent. Examples of topical anti-acne agents include adapalene, azelaic acid, benzoyl peroxide, clindamycin and clindamycin phosphate, doxycycline, erythromycin, keratolytics such as salicylic and retinoic acid (Retin-A), norgestimate, Included are organic peroxides, retinoids such as isotretinoin and treitinoin, sulfacetamide sodium, and tazarotene. Certain anti-acne agents include adapalene, azelaic acid, benzoyl peroxide, clindamycin (e.g. clindamycin phosphate), doxycycline (e.g. doxycycline monohydrate), erythromycin, isotretinoin, norgestimate, Sulfacetamide sodium, tazarotene, etretinate and acitretin.

[00140] In some embodiments, the second API is an antihistamine. Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride, and the like. Examples of local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloro Included are procaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine and dyclonine hydrochloride.

[00141] In some embodiments, the second API is a disinfectant. Examples of antiseptics include alcohols, quaternary ammonium compounds, boric acid, chlorhexidine and chlorhexidine derivatives, iodine, phenols, terpenes, bacteria, disinfectants such as thimerosal, phenol, thymol, benzalkonium chloride , benzethonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol and trimethylammonium bromide.

[00142] In some embodiments, the second API is an analgesic. Examples of analgesics include alfentanil, benzocaine, buprenorphine, butorphanol, butambene, capsaicin, clonidine, codeine, dibucaine, enkephaline, fentanyl, hydrocodone, hydromorphone, indomethacin, lidocaine, levorphanol, meperidine, methadone, morphine, nicomorphine, Included are opiates, oxybuprocaine, oxycodone, oxymorphone, pentazocine, pramoxine, proparacaine, propoxyphene, proxymethacine, sufentanil, tetracaine and tramadol.

[00143] In some embodiments, the second API is an anesthetic. benzyl benzoate; calamine; chloroxylenol; dyclonine; ketamine; menthol; pramoxine; dexivacaine; diamocaine; dibucaine; etidocaine; hexylcaine; levobupivacaine; salts and esters such as bupivacaine HCl, chloroprocaine HCl, diamocaine cyclamate, dibucaine HCl, dyclonine HCl, etidocaine HCl, levobupivacaine HCl, lidocaine HCl, mepivacaine HCl, pramoxine HCl, prilocaine HCl, procaine HCl, proparacaine HCl, propoxycaine HCl, ropivacaine HCl, and tetracaine HCl.

[00144] In some embodiments, the second API is a hemostatic agent. Examples of hemostatic agents include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfanate, rutin and hesperidin.

[00145] A suitable amount of the second API that can be present in the composition is from about 0.1 wt% to about 99.9 wt% of the composition. Generally, the amount of the second API will depend on the specific agent used in the composition. In some embodiments, the API can be up to about 10 wt%, up to about 5 wt%, up to about 2 wt%, up to about 1 wt%, or up to about 0.1 wt% of the composition.

dose
[00146] Dosing may vary depending on the severity of the disease or condition being treated over the course of treatment lasting from several days to several months or until a cure is achieved or a reduction in disease state or reduction in disease symptoms is achieved. and reactivity. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. A person skilled in the medical arts can determine optimum dosages, dosing methodologies and repetition rates. Dosage levels on the order of about 1 ug/kg to about 100 mg/kg of body weight per dose are useful for treating disease. In some embodiments, the dosage is from about 0.001 mg/kg to about 1,000 mg/kg. In some embodiments, the dosage is about 0.001 mg/kg to about 0.01 mg/kg, about 0.001 mg/kg to about 0.1 mg/kg, about 0.001 mg/kg to about 0.25 mg/kg kg, about 0.001 mg/kg to about 0.5 mg/kg, about 0.001 mg/kg to about 0.75 mg/kg, about 0.001 mg/kg to about 1 mg/kg, about 0.001 mg/kg to about 5 mg/kg, about 0.001 mg/kg to about 10 mg/kg, about 0.001 mg/kg to about 50 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.001 mg/kg to about 1, 000 mg/kg, about 0.01 mg/kg to about 0.1 mg/kg, about 0.01 mg/kg to about 0.25 mg/kg, about 0.01 mg/kg to about 0.5 mg/kg, about 0.01 mg /kg to about 0.75 mg/kg, about 0.01 mg/kg to about 1 mg/kg, about 0.01 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg /kg to about 50 mg/kg, about 0.01 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 1,000 mg/kg, about 0.1 mg/kg to about 0.25 mg/kg, about 0 .1 mg/kg to about 0.5 mg/kg, about 0.1 mg/kg to about 0.75 mg/kg, about 0.1 mg/kg to about 1 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 50 mg/kg, about 0.1 mg/kg to about 100 mg/kg, about 0.1 mg/kg to about 1,000 mg/kg, about 0.25 mg/kg to about 0.5 mg/kg, about 0.25 mg/kg to about 0.75 mg/kg, about 0.25 mg/kg to about 1 mg/kg, about 0.25 mg/kg to about 5 mg/kg kg, about 0.25 mg/kg to about 10 mg/kg, about 0.25 mg/kg to about 50 mg/kg, about 0.25 mg/kg to about 100 mg/kg, about 0.25 mg/kg to about 1,000 mg/kg. kg, about 0.5 mg/kg to about 0.75 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 10 mg/kg. kg, about 0.5 mg/kg to about 50 mg/kg, about 0.5 mg/kg to about 100 mg/kg, about 0.5 mg/kg to about 1,000 mg/kg, about 0.75 mg/kg to about 1 mg/kg. kg, about 0.75 mg/kg to about 5 mg/kg, about 0.75 mg/kg to about 10 mg/kg, about 0.75 mg/kg to about 50 mg/kg, about 0.75 mg/kg to about 100 mg/kg, about 0.75 mg/kg to about 1,000 mg/kg, about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 1,000 mg/kg, about 5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 50 mg/kg, about 5 mg/kg to about 100 mg/kg, about 5 mg/kg to about 1,000 mg/kg, about 10 mg/kg to about 50 mg/kg, about 10 mg/kg to about 100 mg/kg, about 10 mg/kg to about 1,000 mg/kg, about 50 mg/kg to about 100 mg/kg, about 50 mg/kg to about 1,000 mg/kg, or about 100 mg/kg to about 1,000 mg/kg. In some embodiments, the dosage is about 0.001 mg/kg, about 0.01 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 1,000 mg/kg. In some embodiments, the dosage is at least about 0.001 mg/kg, about 0.01 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg /kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 50 mg/kg, or about 100 mg/kg. In some embodiments, the dosage is up to about 0.01 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1 mg/kg kg, about 5 mg/kg, about 10 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 1,000 mg/kg. In some embodiments, dosages are based on the amount of API or pharmaceutically acceptable salt thereof (eg, clofazimine) per weight of subject. In some embodiments, dosages are based on the pharmaceutical compositions described herein relative to the weight of the subject.

[00147] Several factors, including, but not limited to, the severity of the subject's disease or disorder, previous treatments, general health and/or age, and other diseases present, may affect the effectiveness of the subject's treatment. can influence the dosage required for The effective dosage of treatment may be increased or decreased during individual treatments. Changes in dosage may occur and become apparent from diagnostic tests. For example, the subject can be monitored after administering the composition. Based on information from monitoring, increased or decreased amounts of the composition can be administered.

situation
[00148] In some embodiments, the pharmaceutical compositions described herein are used to treat a disease or disorder. In some embodiments, the pharmaceutical compositions described herein are used to treat human diseases or disorders. In some embodiments the disease is an inflammatory disease or disorder. In some embodiments, the disease is an inflammation-mediated disease or disorder. In some embodiments, the disease or disorder is a skin disease or disorder. In some embodiments, the disease or disorder is an inflammatory skin disease or disorder. In some embodiments, the disease or disorder is a dermatological disease or disorder. In some embodiments, the disease or disorder is an inflammatory dermatological disease or disorder. In some embodiments, the disease or disorder is associated with Kv1.3 channel overexpression, eg, breast and lung cancer, melanoma, or chronic lymphocytic leukemia. In some embodiments, the disease or disorder is associated with IL-2 hypersecretion. Accordingly, in one aspect, described herein are methods of treating diseases or conditions associated with overexpression of Kv1.3 channels, such as cancer, using the topical formulations described herein. be done. In one aspect, described herein are methods of inhibiting Kv1.3 channels by administering topical formulations described herein. In one aspect, described herein are methods of inhibiting IL-2 secretion or hypersecretion by administering a topical formulation as described herein.

[00149] In some embodiments, the dermatological disease or disorder is rosacea, eczema (i.e., atopic dermatitis), acne, hidradenitis abscess, palmoplantar pustulosis, psoriasis, pustular psoriasis, generalized pustules psoriasis, pyoderma gangrenosum, erosive pustular dermatosis of the scalp, Sweet syndrome, Bowel-associated dermatosis-arthritic syndrome, acute generalized exanthematous pustulosis, pyorrheic keratoderma, Sneddon-Wilkinson disease, IgA Pemphigus, recurrence of pustular lesions in skin folds, infantile acropustulosis, transient neonatal pustulosis, neutrophil-leakage hidradenitis, rheumatic neutrophilic dermatitis, neutrophilic urticaria, dermatitis herpetiformis, line IgA disease (LAD), inflammatory epidermolysis bullosa acquired, alopecia areata, autoimmune angioedema, autoimmune progestational dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, herpetiform Dermatitis, epidermolysis bullosa acquired, erythema nodosum, pemphigoid gestationis, lichen planus, lichen sclerosus, localized scleroderma, pemphigus vulgaris, acute pityriasis lichenoidosis, acute smallpox Pityriasis versiformis, vitiligo, or neutrophilic dermatosis of the dorsum of the foot, basal cell carcinoma, Bowen's disease, congenital erythroblastic porphyria, contact dermatitis, Darier's disease, disseminated superficial rays keratosis hydra, dystrophic epidermolysis bullosa, eczema, epidermolysis bullosa simplex, extramammary Paget's disease, myeloid protoporphyria and X-linked dominant protoporphyria, fungal infections, Hailey-Hailey disease, Herpes simplex, hidradenitis, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucosal pemphigoid, etc. pemphigus, pemphigus vulgaris, pityriasis licheniformis, pityriasis pilaris, plantar warts, sunburn multiforme, pyoderma gangrenosum, scabies, herpes zoster, Squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema or any combination thereof.

[00150] In some embodiments, the pharmaceutical compositions described herein are used to treat psoriasis, keratosis, eczema, rosacea, acne vulgaris, dermatitis, pruritus, seborrhea, skin cancer, Used to treat inflammation, other skin disorders that respond to acitretin or etretinate, and combinations thereof. In some embodiments, the pharmaceutical compositions described herein are used to treat psoriasis, vitiligo, lupus erythematosus, eczema, chronic eczema, dermatitis and contact dermatitis.

[00151] In some embodiments, the pharmaceutical compositions described herein are used to treat psoriasis. In some embodiments, the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythroderma psoriasis, or any combination thereof. In some embodiments, psoriasis is mild. In some embodiments, psoriasis is moderate. In some embodiments, psoriasis is severe. Skin disorders vary widely in symptoms and severity, can be temporary or permanent, and can be painless or painful. Some may be situational, others may be hereditary. Some skin conditions are not serious, but others can be life-threatening.

[00152] In one embodiment, described herein are methods of treating a disease or disorder in a subject in need thereof. In some embodiments, the pharmaceutical compositions described herein are administered to a subject's skin, eg, scalp, face, elbow, knee, arm, leg, back, eg, hip, and the like. In some embodiments, the subject is a mammal, such as a pet (eg, dog, cat, pig) or human. In some embodiments, the subject is human. In some embodiments, the human is 10 years old or younger. In some embodiments, the human is 21 years old or younger. In some embodiments, the human is 21 years of age or older. In some embodiments, the human is 30 years of age or older. In some embodiments, the human is 40 years of age or older. In some embodiments, the human is 50 years of age or older. In some embodiments, the subject has skin lesions of about 2-10% of body surface area. In some embodiments, the subject has skin lesions of about 1-20% of body surface area. In some embodiments, the subject has skin lesions of about 1-40%, 5-20%, 5-30%, 10-20%, 2-15%, 2-10%, or 1-20% of body surface area have parts. In some embodiments, the subject has skin lesions of at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% of body surface area. In some embodiments, the subject has skin lesions up to about 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 80% of body surface area have parts.

[00153] The following examples are used to illustrate the disclosure and should not be considered as limiting the scope of the disclosure. The terms Transcutol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monoethyl ether are art-recognized and are used interchangeably herein to denote compounds of the formula: EtOCH ₂ CH ₂ OCH ₂ CH ₂ OH. used for

Example 1: Clofazimine solubility in aqueous media
[00154] Clofazimine was added to various aqueous media at various pH values (2-5 mL) in 10 mL glass vials with stirring at 25°C. The suspension was stirred at 25° C. for an additional 24 hours when no further dissolution could be observed. When the API still appeared to dissolve, the suspension was stirred for an additional 24 hours at 25°C. This cycle was repeated until no further lysis could be observed. The suspension was then centrifuged and the supernatant filtered by microfiltration. The filtrate was diluted, the clofazimine content was determined by HPLC and the solubility was recorded and shown in Table 5.

Example 2: Clofazimine Solubility in Fatty Acids
[00155] Clofazimine was dissolved in fatty acids at 25°C and the solubility was recorded and shown in Table 6.

Example 3: Clofazimine Solubility in Various Solvents
[00156] Clofazimine was added to various solvents (2-5 mL) in 10 mL glass vials with stirring at 25°C. The suspension was stirred at 25° C. for an additional 24 hours when no further dissolution could be observed. When the API still appeared to dissolve, the suspension was stirred for an additional 24 hours at 25°C. This cycle was repeated until no further lysis could be observed. The suspension was then centrifuged and the supernatant filtered by microfiltration. The filtrate was diluted, the clofazimine content was determined by HPLC and the solubility was recorded and shown in Table 7.

Example 4: Skin Permeability of Clofazimine Preparations
[00157] The permeability in mouse skin of the clofazimine preparations described in Examples 5-14 was evaluated.

[00158] Experiments were performed in an independent vertical Franz stirred cell at 32°C ± 0.5°C and a rotation speed of 100 rpm. The receptor compartment volume was 7 mL and the diffusion area was 3.14 cm ² . The receptor compartment was filled with saline solution. The skin of NU/NU nude mice was mounted so that the inner surface of the skin faced the saline diffusion solution (ensured that there were no air bubbles) and the stratum corneum was exposed to the atmosphere. The clofazimine test preparation (0.5 g) was applied to the skin and exposed for 4 hours, after which the skin was removed from the device and cleaned by wiping with ethanol. The endothelial layer was isolated and the stratum corneum was discarded. The endothelial layer was then cut into small pieces, transferred to a 100 mL volumetric flask and extracted by soaking in acetonitrile for 24 hours. The clofazimine content in the acetonitrile extract was determined by HPLC and the clofazimine content per unit area of epidermis was calculated. Figure 9 shows a cartoon representation of the equipment used for this procedure. This procedure was used to evaluate skin permeation of the clofazimine preparations described in Examples 5-14.

Example 5: Skin Permeability of Clofazimine Solutions
[00159] Permeability of clofazimine solutions in mouse skin was evaluated. Clofazimine (100 mg) was dissolved in 8 different organic solvents (99.9 g); -15). Skin permeability of various clofazimine solutions was tested in the NU/NU nude mouse model as described in Example 4. The results are shown in Table 8 and the graph in FIG.

Example 6: Skin Permeability of Clofazimine Gel Preparations
[00160] Permeability of clofazimine gel preparations in mouse skin was evaluated. Clofazimine (100 mg; 0.1%, wt) was dissolved in a variety of different organic solvents (9.9 g): Transcutol, PEG 400, Labrasol (or PEG-8 caprylic/capric glycerides), and Tween 80. A gel containing carbomer 940 (0.5 g; 0.5 wt %) in water was prepared and the pH was adjusted to 7.0 by the addition of triethanolamine (TEA). The clofazimine solution was added to the carbomer gel while stirring until a uniform dispersion was obtained; see Table 9 for amounts (propylene glycol and laurocapram were also evaluated, but the clofazimine precipitated and each formed a separate layer). .

[00161] As described in Example 4, the skin permeability of various clofazimine gel preparations was tested in the NU/NU nude mouse model. The results are shown in Table 10 and the graph in FIG.

Example 7: Comparison of Skin Permeability of Clofazimine Solution Versus Gel Preparations
[00162] Mouse skin permeation of the various clofazimine formulations described in Example 5 (solution) or 6 (gel preparation) and shown in Table 11 were compared.

[00163] Skin permeability of clofazimine solutions and gels was tested in the NU/NU nude mouse model as described in Example 4. The results are shown in Table 12 and the graph in FIG.

Example 8: Effect of Penetration Enhancers on Skin Permeability of Clofazimine Gel Preparations
[00164] Clofazimine (100 mg) was dissolved in Transcutol (9.9 g). This solution was added to an aqueous solution of carbomer (0.5 g). A penetration enhancer (4 g) was then added and the pH was adjusted to 7.0 by the addition of triethanolamine. The mixture was stirred until a gel formed due to uniform dispersion. Penetration enhancers tested were: 0.05% sodium dodecyl sulfate (SDS), ethanol, DMSO, Tween 80, Tween 20, n-octanol, oleic acid, and lecithin (containing 20-30% phosphatidylcholine), and water ( as a control). Gel formulations are summarized in Table 13.

[00165] As described in Example 4, the skin permeability of various clofazimine gel preparations was tested in the NU/NU nude mouse model. The results are shown in Table 14 and the graph in FIG.

Example 9: Effect of Lecithin Concentration on Skin Permeability of Clofazimine Gel Preparations
[00166] Clofazimine (100 mg) was dissolved in Transcutol (20 g). This solution was added to an aqueous solution of carbomer (0.5). Various amounts of lecithin (containing 20-30% phosphatidylcholine) were then added and the pH was adjusted to 7.0 by addition of triethanolamine. The mixture was stirred until a gel was formed for uniform distribution. Gel formulations are summarized in Table 15.

[00167] As described in Example 4, the skin permeability of various clofazimine solutions was tested in the NU/NU nude mouse model. The results are shown in Table 16 and the graph in FIG.

Example 10: Effect of pH on Skin Permeability of Clofazimine Hydrogel Preparations
[00168] Clofazimine (100 mg) was dissolved in Transcutol (20 g) and added to an aqueous solution of carbomer (0.5 g). Lecithin (containing 20-30% phosphatidylcholine; 5 g) was added and the pH was adjusted to 6.0, 7.0, 8.0, 9.0 or 9.5 by addition of triethanolamine. The mixture was stirred until a gel was formed for uniform distribution. Gel formulations are summarized in Table 17.

[00169] As described in Example 4, the skin permeability of various clofazimine solutions was tested in the NU/NU nude mouse model. The results are shown in Table 18 and the graph in FIG.

Example 11: Effect of Clofazimine Concentration on Permeability of Clofazimine Gel Preparations
[00170] Various amounts of clofazimine were dissolved in Transcutol (20 g) and added to an aqueous solution of carbomer (0.5 g). Lecithin (containing 20-30% phosphatidylcholine; 5 g) was added and the pH was adjusted to 6.0, 7.0, 8.0, 9.0 or 9.5 by addition of triethanolamine. The mixture was stirred until a gel was formed for uniform distribution. Gel formulations are summarized in Table 19.

[00171] As described in Example 4, the skin permeability of various clofazimine solutions was tested in the NU/NU nude mouse model. The results are shown in Table 20 and the graph in FIG.

Example 12: Effect of Carbomer Concentration on Permeability of Clofazimine Gel Preparations
[00172] Clofazimine (100 mg) was dissolved in Transcutol (20 g) and added to various amounts of carbomer (0.5, 0.8 and 1.0%) in water. Lecithin (containing 20-30% phosphatidylcholine; 5g) was added and the pH was adjusted to 7.0 by addition of triethanolamine. The mixture was stirred until a gel was formed for uniform distribution. Gel formulations are summarized in Table 21.

[00173] As described in Example 4, the skin permeability of various clofazimine solutions was tested in the NU/NU nude mouse model. The results are shown in Table 22 and the graph in FIG.

Example 13: Clofazimine Gel Preparation
[00174] Three clofazimine gels containing humectants (as preservatives such as but not limited to propylparaben and methylparaben) and antioxidants (to prevent oxidation, such as but not limited to butylated hydroxytoluene).

[00175] Clofazimine was dissolved in Transcutol and added to the mixture of Tween 80, propylene glycol, glycerin, allantoin, methylparaben, propylparaben and butylated hydroxytoluene, which was stirred uniformly for total dispersion. The pH was adjusted to 6-7 by the addition of triethanolamine to form a dark red transparent hydrogel. Table 23 shows the amounts for each formulation.

Example 14: Clofazimine Cream Preparation
[00176] Three clofazimine creams were prepared.

[00177] Clofazimine and lecithin were dissolved in Transcutol and heated to 80°C. A mixture of petrolatum, liquid paraffin and glyceryl monostearate was added and stirred until completely dissolved. A solution of sodium lauryl sulfate in an appropriate amount of water was heated to 85°C until complete dissolution. Methylparaben, Propylparaben and BHT (quantity) were dissolved in propylene glycol and then added to the sodium lauryl sulfate solution and stirred until complete dissolution. This mixture was then added to the clofazimine solution with stirring while maintaining the temperature at 85°C. After uniform stirring, the temperature is gradually lowered to room temperature to obtain the desired cream. Table 24 shows the amount of each preparation.

Example 15: Compatibility of clofazimine and excipients
[00178] Clofazimine was dissolved in different excipients in different weight ratios and the mixtures were then subjected to conditions of 60°C for 3 days. Total decomposition impurities were measured by HPLC and summarized in Table 25 below. Excipients were classified as follows according to the results.

[00179] Clofazimine is readily hydrolyzed and oxidized. Excipients suitable for use in preparing stable gels, ointments, or emulsions of clofazimine include labrasol, Transcutol, propyl glycol, and glycerin. It has been found that lipid excipients such as PEG 3350, stearyl alcohol, petrolatum, and liquid paraffin can provide improved chemical stability of clofazimine.

Example 16: Clofazimine Formulation
[00180] The topical formulations in Table 26 were prepared by the following. Clofazimine was dissolved in a mixture of stearyl alcohol, liquid paraffin and petroleum jelly at a temperature of 80° C., then the resulting mixture was stirred and cooled to room temperature. A formulation base was prepared in the same way. No clofazimine crystals were observed in the three formulations by polarized light microscopy. This means that the clofazimine has dissolved in the base.

Example 17: Clofazimine Treatment on Imiquimod-Induced Psoriasis-Like Mouse Model
[00181] Fifty C57BL/6J mice were randomly divided into five groups: naive group, model group, formulation 1-3 groups. The backs of all mice were shaved. The naive group was the negative group and served as a blank control. The other four groups received topical application of 5% imiquimod cream (sold under the trade name Aldara®) once daily for one week. At the same time, each group was administered Formulation Base or one of Formulations 1-3, respectively, once daily for 7 consecutive days. During the last 3 days, changes in skin lesions were observed and evaluated by the PASI method.

[00182] PASI method: Scores for erythema, scale and infiltration thickening in skin lesions were scored respectively, and the sum of the three scores was the total score.

[00183] PASI scoring criteria: 0, none; 1, mild; 2, moderate; 3, severe; 4, extremely severe.

[00184] The results are shown in Table 27 below. A therapeutic effect of clofazimine on an imiquimod-induced psoriasis-like mouse model was confirmed.

Example 18: Clofazimine Formulation
[00185] The topical formulations in Table 28 were prepared by the following. Clofazimine was dissolved in a mixture of stearyl alcohol, liquid paraffin and petroleum jelly at a temperature of 80° C., then the resulting mixture was stirred and cooled to room temperature. Clofazimine crystals were observed in two formulations (formulations 4 and 5) by polarized light microscopy. This means that clofazimine was not completely dissolved in the base.

Example 19: Stratum corneum penetration effect of various topical formulations
[00140] This experiment illustrates the stratum corneum penetration effect of various topical formulations on nude mouse skin.

[00186] Experiments were performed in an independent vertical Franz stirred cell at 32°C ± 0.5°C and a rotation speed of 100 rpm. The receptor compartment volume was 7 mL and the diffusion area was 3.14 cm2. The receptor compartment was filled with saline solution. The skin of NU/NU nude mice was mounted so that the inner surface of the skin faced the saline diffusion solution (ensured that there were no air bubbles) and the stratum corneum was exposed to the atmosphere. The clofazimine test preparation (0.5 g) was applied to the skin and exposed for 4 hours, after which the skin was removed from the device and cleaned by wiping with ethanol. The endothelial layer was isolated and the stratum corneum was discarded. The endothelial layer was then cut into small pieces, transferred to a 100 mL volumetric flask and extracted by soaking in acetonitrile for 24 hours. The clofazimine content in the acetonitrile extract was determined by HPLC and the clofazimine content per unit area of epidermis was calculated.

[00187] As illustrated in Figure 10, the results show that increasing the clofazimine content in the base increases its content within the stratum corneum, but peaks with Formulation 3 (clofazimine completely dissolved in the base). , showed no further enhancement by Formulations 4 and 5 (clofazimine incompletely dissolved in the base). This result indicated that only dissolved clofazimine was able to penetrate the stratum corneum.

Example 20: Clofazimine Formulation
[00188] The topical formulations in Table 29 were prepared by the following. Clofazimine was dissolved in a mixture of liquid paraffin and petroleum jelly at a temperature of 80° C., then the resulting mixture was stirred and cooled to room temperature. No API crystals were observed by polarized light microscopy in the three formulations. This means that the API has dissolved into the base.

[00189] The in vivo PK profile of formulations 6-9 is examined by applying clofazimine topical formulations to minipig skin.

Example 21: Inhibition of Kv1.3 Channels in Human Jurkat E6-1 Cells
[00190] Kv1.3-type voltage-gated potassium channels are widely expressed in many cell types, both normal and cancer. The activity of Kv1.3 channels plays an important role in setting resting membrane potential, cell proliferation, apoptosis and dose regulation. Altered expression of Kv1.3 channels has been found in several cancer diseases such as breast, colon, pancreas, smooth muscle, skeletal muscle, lung, kidney and prostate cancer. Inhibitors of Kv1.3 channels have clinical application in the treatment of several cancer disorders characterized by overexpression of Kv1.3 channels, such as breast and lung cancer, melanoma, or chronic lymphocytic leukemia. Evidence.

[00191] The effect of clofazimine on channel activity was studied by applying a voltage ramp protocol to the human Jurkat E6-1 cell line. Cell lines were cultured in RPMI 1640 medium containing 10% FBS and passaged. A potential ramp depolarizing the cell membrane from −100 mV to 100 mV was applied every 2 s; the ramp duration was 50 ms and the holding potential was −70 mV. Upon application of the voltage ramp protocol, Kv1.3 currents in Jurkat E6-1 cells were stabilized prior to addition and detection of test formulations. Formulations of clofazimine at 0.3 μM, 1 μM, 3 μM, 10 μM, and 20 μM in DMSO are shown in Table 30 below. Clofazimine was found to inhibit Kv1.3 currents in Jurkat E6-1 cells with a suitable IC50 value of 3.3 μM±657.0 nM.

Example 22: Inhibition of IL-2 Secretion of Activated Jurkat Cells
[00192] Jurkat cells were divided into five groups: negative (no treatment), positive control (PMA + PHA), and formulations of clofazimine at 1, 3, and 10 μM in DMSO. In each group, Jurkat cells were incubated with the corresponding formulation. After 24 h, IL-2 secretion was detected by ELISA. IL-2 secretion in the positive control group was markedly increased; it was markedly inhibited by clofazimine preparations (FIG. 11).

Example 23: Clofazimine Formulations for Treating Psoriasis in Mice

[00193] Benbitimod Cream (1%) (Zhonghao Pharma, China), Calcipotriol Ointment (15g: 75mg) (Daivonex, LEO Pharma A/S, Denmark), Formulation 10 (Clofazimine 0) in imiquimod-induced psoriasis-like mice .01%), Formulation 11 (clofazimine 0.03%) and Formulation 12 (clofazimine 0.1%) once daily topical treatment. A psoriasis-like skin inflammation mouse model was generated by topical application of imiquimod cream (5%) (Aldara, INOVA Pharmaceuticals, Singapore) to the backs of mice daily for 9 consecutive days.

[00194] Benbitimod cream (1%) was found to significantly reduce skin lesions. Calcipotriol ointment (15 g: 75 mg) improved skin erythema, but caused skin damage, resulting in peeling and thickening due to skin damage, resulting in no improvement in terms of scale and skin thickening. Formulations 10-12 (clofazimine 0.01%, 0.03% and 0.1%) significantly reduced skin lesions in a concentration-dependent manner. The efficacy of formulation 12 (0.1%) was superior to benbitimod cream (0.1%) in reducing skin irritation.

[00195] Benbitimod cream (1%), calcipotriol ointment (15 g: 75 mg) and formulations 10-12 (clofazimine 0.01%, 0.03% and 0.1%) each treated microabscesses in the cuticle. , reduced cuticle thickening, and reduced inflammatory infiltration into the dermis. Benbitimod cream was somewhat superior to calcipotriol cream in these respects. The efficacy of formulations 10 and 11 (clofazimine 0.01% and 0.03%) was comparable to calcipotriol ointment and the efficacy of formulation 12 (0.1%) to benbitimod cream.

Example 24: Clofazimine Blood Concentrations in Minipigs
[00196] A study was conducted to evaluate blood concentration-time curves following topical application of Formulations 10-12 (clofazimine 0.01%, 0.03% and 0.1%) in Bama minipigs. 24 Bama minipigs (12 males and 12 females) were randomly divided into 4 groups (n=6), 3 groups receiving formulations 10-12 (clofazimine 0.01%, 0.03%). and 0.1%). Topical application of Formulation 11 (clofazimine 0.03%, bid, 12h interval, total of 9 applications) was repeated for a fourth group. For the top four groups, formulations 10-12 were applied to 5% body surface area of Bama minipigs, ⁱ . ² ) was applied. Blood samples were collected at baseline, 0.167, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours after drug application for the single dose group. Blood samples in the repeat dose group were collected before 5 ^th to 8 ^th topical application, 0.167, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours after drug application. A validated LC-MS/MS method was used to determine concentrations of clofazimine in plasma and to calculate pharmacokinetic parameters (standard curve range for clofazimine is 0.0100-10.0 ng/mL).

[00197] For the single dose groups, a few samples in the 0.01% and 0.1% groups showed very low levels of clofazimine (near the detection limit of the instrument). No clofazimine was detectable in most of the samples. Very low levels of clofazimine could be detected in plasma in the repeat dose group. No significant gender differences in clofazimine absorption were observed.

Example 25: Clofazimine Tissue Distribution in Minipigs
[00198] A study was performed to evaluate the pharmacokinetics and tissue distribution after single-dose topical application of Formulation 11 (clofazimine 0.03%) in Bama minipigs. 24 Bama minipigs were divided into 6 groups (n=4) and each group of minipigs received a single topical application of Formulation 11 (0.03%) at a dose of 1.5 mg ointment/ ^cm2 . . Blood samples, epidermis, dermis, subcutaneous tissue and subcutaneous muscle were collected at 0.5, 4, 24, 48, 72 and 96 hours (one time point per group) after drug application. A validated LC-MS/MS method was used to determine the concentrations of clofazimine in plasma, epidermis, dermis, subcutaneous tissue and subcutaneous muscle and to calculate pharmacokinetic parameters (standard curve range for clofazimine is 0.0100 to 10.0 ng/mL).

[00199] At each time point, the distribution trend of clofazimine was as follows: epidermis>dermis>subcutaneous tissue≈subcutaneous muscle>plasma. The median time to reach peak epidermal and subcutaneous muscle concentrations was approximately 0.5 h, while the median time to reach peak dermal and subcutaneous tissue concentrations was approximately 4 h. Concentrations of clofazimine in the epidermis and dermis were much higher than in the subcutaneous tissue and muscle, indicating that clofazimine was distributed mainly in the epidermis and dermis and was not absorbed into the blood. The results of the study are shown in Table 31 below.

Example 26: Dermal Irritation in Rabbits
[00200] A study was conducted to evaluate dermal irritation after 28 days of topical treatment of Japanese White Rabbits with Formulations 11 and 12. 24 rabbits (12 males and 12 females) were divided into 6 groups (n=4), including 3 intact skin groups and 3 injured skin groups. Plain ointment Formulation 11 (0.03%) and Formulation 12 (0.1%) at a dose of 0.4 g/rabbit were shaved on the right side of damaged and unblemished skin. The area was applied twice daily. A similar amount of plain saline was applied to the left armpit for 28 consecutive days as a control. The general condition of all groups was good, and no skin irritation was observed at the administration site.

Example 27: Cutaneous Phototoxicity in Guinea Pig Back Skin
[00201] A study was conducted to evaluate the skin phototoxicity of Formulations 11 and 12 in guinea pigs. 40 Hartley guinea pigs (20 males and 20 females) were divided into 5 groups (n=8). Two sections of 5 x 5 cm/site of back skin were shaved. Plain saline (negative control, 0.18 mL/armpit), 0.1% 8-MOP (positive control, 0.2 mL/armpit), plain ointment (0.18 g/armpit), formulation 11 (0 0.03%, 0.18 g/armpit) and Formulation 12 (0.1%, 0.18 g/armpit) were applied to shaved skin. After 30 minutes, the drug was washed off, the right side was irradiated with UV at 10 J/cm ² for 18 minutes, and the left side was covered with a sheet of aluminum foil (non-irradiated area). Skin reactions were evaluated 1, 24, 48 and 72 h after stimulation. No toxic reactions or phototoxicity were observed.

Example 28: Cutaneous phototoxicity in guinea pig parietal skin
[00202] A study was conducted to evaluate the skin phototoxicity of Formulations 11 and 12 in guinea pigs. 50 Hartley guinea pigs (25 males and 25 females) were divided into 5 groups (n=10). The top skin (4×4 cm) of each subject was shaved. Plain saline (negative control, 0.18 mL), 1% TCSA (positive control, 0.2 mL), plain ointment (0.18 g), formulation 11 (0.03%, 0.18 g) and formulation 12 (0.1%, 0.18 g) was applied to shaved skin for 5 days (1 time/d). Two weeks after the last sensitization, guinea pigs were challenged. NS (0.18 mL/armpit), 0.5% TCSA (0.03 mL/armpit), plain ointment (0.18 g/armpit), Formulation 11 (0.03%, 0.18 g/armpit) and Formulation 12 (0.1%, 0.18 g/armpit) was applied to each armpit of the shaved back skin. After 30 minutes, the drug was washed off, the right armpit was irradiated with UV rays at 10 J/cm ² for 19 min, and the left armpit was covered with a sheet of aluminum foil. Skin reactions were evaluated at 1, 24, 48 and 72 h after challenge. No photosensitivity reactions were observed.

Example 29: Anaphylaxis in Guinea Pigs
[00203] A study was conducted to evaluate active cutaneous anaphylaxis of Formulations 11 and 12 in guinea pigs. 50 Hartley guinea pigs (25 males and 25 females) were divided into 5 groups (n=10). The left flank of the back skin of each guinea pig was shaved. Plain saline (negative control, 0.18 mL), 1% DNCB (positive control, 0.2 mL), plain ointment (0.18 g), formulation 11 (0.03%, 0.18 g) and formulation 12 (0.1%, 0.18 g) was applied to shaved skin on days 1, 8 and 15. 14 days after the last sensitization, the guinea pigs were challenged. NS (0.18 mL), 0.5% DNCB (0.2 mL), plain ointment (0.18 g), 0.03% formulation 11 (0.18 g) and 0.1% formulation 12 (0.18 g) was applied to the right side of the shaved back skin. The administration site of each group was covered with gauze and cellophane for about 6 hours for sealing and fixation, and then the gauze and cellophane were removed, after which skin reactions were evaluated at 1, 24, 48, and 72 h. Results for active cutaneous anaphylaxis were negative.

Example 30: Stability of Formulations 10-12
[00204] Acceleration and long-term stability studies were performed on Formulation 10, Formulation 11, and Formulation 12. The assay procedure follows the USP 40 clofazimine capsule method and is detailed in Table 32 below.

[00205] Impurities were determined by HPLC. HPLC parameters and procedures are shown below and in Table 33. Phenylsilane-bonded silica gel was used as packing material (Agilent, ZORBAX SB Phenyl 250 mm 4.6 mm, 5 μm or equivalent column). Mobile phase A, acetonitrile and methanol, was added to pH 3.0 buffered salt solution (4.5 g sodium dodecyl sulfate, 1.7 g tetrabutylammonium hydrogen sulfate and 1.8 g disodium hydrogen phosphate dodecahydrate in 900 mL water). and adjusted the pH value to 3.0 with 8.5% phosphoric acid, then diluted to 1 L with water). The flow rate was 1.0 mL/min. The detection wavelength was 280 nm. Gradient elution was performed at column temperature 30 as shown in Table 33 below.

[00206] The results of the experiments are shown in Tables 34-39 below. Accelerated stability experiments were performed at 40°C and 75% RH. Long-term stability experiments were performed at 25°C and 60% RH. The abbreviation "NT" means that the sample was not tested at that time.

Example 31: Administration of topical clofazimine formulations described herein to patients
[00207] This study is a single-center, double-blind, randomized, placebo-controlled clinical trial of the efficacy and safety of clofazimine ointment in the treatment of psoriasis vulgaris. The study will enroll approximately 32 subjects. Subjects were randomly assigned to four groups of eight in a 1:1:1:1 ratio.

[00208] Inclusion criteria for this study may include one or more of the following:
1. Willing to participate in clinical research, fully understanding and informed of the study, signing informed consent, and able to voluntarily follow and complete all study procedures;
2. No gender restriction, age 18-65 years at informed consent signing;
3. Female patients must not be pregnant, must not intend to become pregnant during the study, and must know effective contraceptive methods during the study;
4. Male patients must abstain from intercourse during the study or agree to use contraception;
5. Clinically diagnosed plaque psoriasis for at least 6 months;
6. Total skin lesion area: 2-10% of body surface area;
7. Investigator's Global Assessment (PGA) ≥2;
8. A skin lesion diameter ≧3 cm at the target site is observed and is compatible with topical drug treatment;
9. Pre-existing conditions such as heart disease, liver, kidney, gastrointestinal, nervous system, psychiatric and metabolic disorders.

[00209] Exclusion criteria for this study may include one or more of the following:
1. Exclusions based on target disease (a). currently diagnosed with uncommon psoriasis (e.g., erythroderma, pustular, and arthritic psoriasis), and advanced plaque psoriasis;
(b). Psoriasis caused by drugs (e.g., lithium agents, beta blockers, antimalarials, angiotensin conversion inhibitors (ACEI), etc.);
(c). Psoriatic lesions greater than 10% body surface area;
(D). Palm-plantar psoriasis;
(e). Patients with other skin diseases that may interfere with the assessment of their condition;
(f). Patients with severe skin breakage and infection at the lesion site;
2. Exclusion based on medical history and concomitant disease (a) Severe organ and systemic disease, e.g., cardiovascular (e.g., heart failure, unstable angina), liver (e.g., cirrhosis of the liver), kidney (e.g., renal failure) , pulmonary (e.g. chronic obstructive pulmonary disease), endocrine glands (e.g. Cushing's syndrome, diabetes, obesity (BMI>25)), osteoarthritis, gastrointestinal, nervous and hematological diseases, etc., and other autoimmune diseases , has a malignant tumor, or the investigator considers other conditions ineligible to participate in this study;
(b). Any of the following abnormalities found in clinical trials during screening: peripheral blood leukocyte count <3.0 x 109/L or >15 x 109/L; hemoglobin <90 g/L; platelets <100 x 109/L; ALT and AST >1.5 times upper limit of normal; serum creatinine and BUN higher than upper limit of normal.
(c). Conditions that may affect patient compliance, e.g., extended work or vacation, psychiatric illness;
3. Exclusion based on previous and current treatment (a). received topical psoriasis medications (e.g., glucocorticoids, vitamin D3 derivatives, retinoates, dianthracene, coal tar, salicylic acid, calcineurin inhibitors and topical immunomodulatory ingredients) within 2 weeks prior to screening;
(b). Received phototherapy (UVA, UVB) within 4 weeks prior to screening;
(c). received systemic medications (retinoids, MTX, cyclosporine, glucocorticoids, Chinese patent medicines, etc.) within 4 weeks prior to screening;
(d). Received systemic biologics known to act on psoriasis (marketed or not) within a defined period prior to screening: ustekinumab, 32 weeks prior to first treatment; secukinumab, first dose Efalizumab, 18 weeks prior to first dose; Alefacept, Infliximab, Adalimumab, 8 weeks prior to first treatment; Etanercept, 4 weeks prior to first dose; For other drugs, 4 weeks/5 halves prior to first dose period (whichever is longer);
(e). Participating in another clinical study or will begin treatment in this study less than 3 months after completion of drug treatment in a previous clinical study;
(f). Regular use of botanicals or sedatives, sleeping pills, tranquilizers and other addictive drugs;
4. The participant has a history of allergy to the active ingredient or excipient of the study drug;
5. Pregnant women, breastfeeding women, women with a positive pregnancy test at entry or prior to administration of study drug;
6. Participants have other conditions that make them unsuitable for entry, at the investigator's discretion.

[00210] Topical clofazimine formulations are administered in three doses (eg, formulations 10, 11 and 12). A placebo (blank matrix) is also administered.

[00211] Therapeutic intervention: For external skin, after cleansing the affected area and drying the skin, avoiding contact with normal skin, apply an appropriate amount of this product to the affected area for one day. Apply once in the morning and evening. At least 1 hour after each application, the skin lesions can be wiped or cleaned, including treatment of new psoriatic skin lesions. For all initially affected areas, administration must continue until the end of the study, even after lesion resolution. For the purposes of this study, the drug cannot be applied to the face, axillae, vulva and other areas.

[00212] Study Process: This study is divided into three phases:
- Screening period;
Treatment Phase (1, 4, 8 weeks, until unacceptable toxicity occurs, participant or physician decides to stop treatment, or other reasons specified by protocol, whichever occurs first) ;
・Revisit period after cessation of drug use (2, 4 weeks)
[00213] Endpoints: Primary endpoints are PASI75 and PGA, secondary endpoints are PASI50 and PASI90, and safety endpoints include ADRs and their occurrence.

[00214] Data statistics are performed by biostatisticians using statistical software. All hypothesis tests were two-sided and P<0.05 was considered statistically significant.

[00215] Process diagram. A representative process diagram is shown in Scheme 1 below:

[00216]

[00217] For the purposes of this study, all participants signed an informed consent form prior to undertaking any study-related tests, women of childbearing age underwent a negative urine pregnancy test, and were tested for efficacy during the study. provided with effective contraception. Routine blood tests such as hemoglobin, red blood cell count, white blood cell count, and platelet count can be included. Blood biochemistry tests such as alanine aminotransferase, aspartate aminotransferase, urea nitrogen, creatinine, triglycerides, and total cholesterol can be included.

[00218] Typical All-Visit Arrangement: Participant visits may be at baseline, weeks 1, 4, and 8 on medication, and weeks 2, 4 after drug withdrawal. If disease progresses between two visits, participants can contact the investigator at any time and visit the hospital in a timely manner. If the investigator determines that the patient has relapsed, the drug will be administered again.

Example 32: Formulation of API of Table 1
[00219] Formulations are made by replacing clofazimine in Formulations 1-12 with APIs (other than clofazimine) in Table 1. The preparation procedures are the same as those for Formulations 1-12 listed in the respective examples.

Claims (116)

A topical pharmaceutical composition comprising:
(a) a compound, or a pharmaceutically acceptable salt thereof, present in an amount up to about 2% of the total weight of the composition, wherein the compound is of formula (I):

(In the formula,
Each of R ¹ , R ² and R ³ is independently an aryl radical selected from the group consisting of phenyl, chlorophenyl, lower alkylphenyl and lower alkoxyphenyl; C ₁ -C ₁₂ alkyl; C ₃ -C ₈ cyclo alkyl; or C ₁ -C ₁₁ heteroalkyl, wherein each of aryl, alkyl, cycloalkyl, and heteroalkyl is substituted or unsubstituted;
R ₄ represents a hydrogen atom or a halogen atom;
R ₅ represents a hydrogen atom or a halogen atom)
A compound or a pharmaceutically acceptable salt thereof having the structure of;
and (b) a pharmaceutical composition comprising at least one solubilizer and formulated for topical administration. 2. The pharmaceutical composition of Claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is dissolved in at least one solubilizer. A topical pharmaceutical composition comprising:
(a) a compound, or a pharmaceutically acceptable salt thereof, present in an amount up to about 10.0% of the total weight of the composition, wherein the compound is of formula (I):

(In the formula,
Each of R ¹ , R ² and R ³ is independently an aryl radical selected from the group consisting of phenyl, chlorophenyl, lower alkylphenyl and lower alkoxyphenyl; C ₁ -C ₁₂ alkyl; C ₃ -C ₈ cyclo alkyl; or C ₁ -C ₁₁ heteroalkyl, wherein each of aryl, alkyl, cycloalkyl, and heteroalkyl is substituted or unsubstituted;
R ₄ represents a hydrogen atom or a halogen atom;
R ₅ represents a hydrogen atom or a halogen atom)
A compound or a pharmaceutically acceptable salt thereof having the structure of;
and (b) comprising at least one solubilizing agent, wherein the compound or a pharmaceutically acceptable salt thereof is dissolved in the at least one solubilizing agent, and the pharmaceutical composition is formulated for topical administration. pharmaceutical composition. Claims 1-3, wherein the formulation retains about 90 to about 110% w/w of the initial amount of the compound or pharmaceutically acceptable salt thereof after being stored at 40°C and 75% RH for 6 months. The pharmaceutical composition according to any one of The total amount of impurities in the formulation is 2% w/w or less based on the initial amount of the compound or its pharmaceutically acceptable salt after being stored at 40°C and 75% RH for 6 months. 5. Pharmaceutical composition according to any one of 1 to 4. 6. The pharmaceutical composition according to any one of claims 1-5, wherein ^R1 is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. 7. The pharmaceutical composition according to any one of claims 1-6, wherein ^R3 is phenyl, chlorophenyl, lower alkylphenyl, or lower alkoxyphenyl. 8. The pharmaceutical composition according to any one of claims 1-7, wherein ^R2 is an ethyl, propyl, butyl, pentyl, hexyl, heptyl, decyl, cyclohexyl, or cycloheptyl radical. R ² is ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, heptyl, 1,3-dimethylbutyl, sec-butyl, 1,1-dimethylethyl (t-butyl), 3 , 5,5-trimethylpentyl, n-dodecyl, n-decyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,5-dimethylcyclohexyl or cycloheptyl radicals. Pharmaceutical composition as described. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein each of ^R4 and ^R5 is hydrogen. The compounds are clofazimine, 2-(p-chloro-anilino)-3-cyclohexylimino-5-(p-chlorophenyl)-3,5-dihydro-phenazine, 2-anilino-3-cyclohexylimino-5-phenyl-3 ,5-dihydrophenazine. 12. The pharmaceutical composition according to any one of claims 1-11, wherein the compound or a pharmaceutically acceptable salt thereof is clofazimine. 13. A pharmaceutical composition according to any one of claims 1-12, wherein the compound or a pharmaceutically acceptable salt thereof is present in an amount up to about 1.5% of the total weight of the composition. 13. The pharmaceutical composition according to any one of claims 1-12, wherein the compound or a pharmaceutically acceptable salt thereof is present in an amount up to about 1% of the total weight of the pharmaceutical composition. 13. A medicament according to any one of claims 1 to 12, wherein the compound or a pharmaceutically acceptable salt thereof is present in an amount of about 0.005% to 0.5% of the total weight of the pharmaceutical composition. Composition. 13. Any one of claims 1-12, wherein the compound or a pharmaceutically acceptable salt thereof is present in an amount from about 0.01% to about 0.1% of the total weight of the pharmaceutical composition. pharmaceutical composition. 17. The pharmaceutical composition according to any one of claims 1-16, which is non-aqueous. A topical pharmaceutical composition comprising:
(a) an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof, present in an amount up to about 10.0% of the total weight of the composition, wherein the active pharmaceutical ingredient is about 4.0% or greater; and (b) at least one solubilizer, wherein the API or pharmaceutically acceptable salt thereof comprises at least one A pharmaceutical composition dissolved in a solubilizing agent and wherein the pharmaceutical composition is formulated for topical administration. 19. The pharmaceutical composition of Claim 18, wherein the API or pharmaceutically acceptable salt thereof is present in an amount up to about 1.5% of the total weight of the composition. 19. The pharmaceutical composition of claim 18, wherein the API or pharmaceutically acceptable salt thereof is present in an amount up to about 1% of the total weight of the pharmaceutical composition. 19. The pharmaceutical composition of Claim 18, wherein the API or pharmaceutically acceptable salt thereof is present in an amount of about 0.005% to 0.5% of the total weight of the pharmaceutical composition. 19. A pharmaceutical composition according to claim 18, wherein the API or a pharmaceutically acceptable salt thereof is present in an amount from 0.01% to 0.1% of the total weight of the pharmaceutical composition. APIs include hesperetin, lormetazepam, naringenin, cinchonidine, alprenolol, propranolol, ketoprofen, clofibric acid, naproxen, warfarin, apigenin, diazepam, quinine, quetiapine, rosiglitazone, clotiazepam, tramadol, fenbufen, chlorphenamine, pyrilamine, venrafa Xin, brompheniramine, diphenhydramine, chrysin, valsartan, penbutolol, diltiazem, ibuprofen, bupivacaine, flurbiprofen, progesterone, chlordiazepoxide, trazodone, haloperidol, glimepiride, abiraterone, indomethacin, clopidogrel, flurazepam, duloxetine, nortriptyline, celecoxib, nilotinib , atorvastatin, maprotiline, fluoxetine, diclofenac, amitriptyline, imipramine, loratadine, cyproheptadine, chlorpromazine, sertraline, flufenamic acid, miconazole or rimonabant. 23. The API of claims 18-22, wherein the API has a calculated logP in octanol-water of about 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5 or greater. A pharmaceutical composition according to any one of claims. Claims 18-22, wherein the API has a calculated logP in octanol-water within the range of about 4.0, 4.5, 5.0, 5.5 or 6 to about 7, 8, 9 or 10 The pharmaceutical composition according to any one of 26. The pharmaceutical composition according to any one of claims 18-25, which is non-aqueous. The at least one solubilizer is one of: (i) saturated hydrocarbons or mixtures thereof, (ii) fatty alcohols having at least 9 carbons, (iii) fatty acids having at least 9 carbons. 18. A pharmaceutical composition according to any one of claims 1 to 17, comprising one or more. The at least one solubilizer is: (i) a petroleum jelly, (ii) one or more alkanes each independently having at least 9 carbons, (iii) a fatty alcohol having at least 9 carbons, and (iv) one or more of fatty acids having at least 9 carbons. 18. Any one of claims 1-17, wherein the at least one solubilizing agent comprises (i) petroleum jelly, (ii) one or more alkanes each independently having at least 9 carbons, or both. The pharmaceutical composition according to . The at least one solubilizer comprises (i) petroleum jelly, (ii) one or more alkanes each independently having at least 9 carbons, and (iii) a fatty alcohol having at least 9 carbons 18. The pharmaceutical composition according to any one of claims 1-17. 31. The pharmaceutical composition according to any one of claims 1-30, wherein the solubilizer is present in an amount from about 50% to about 99.9% of the total weight of the pharmaceutical composition. 31. The pharmaceutical composition of any one of claims 1-30, wherein the solubilizer is present in an amount from about 80% to about 99.9% of the total weight of the pharmaceutical composition. 31. The pharmaceutical composition of any one of claims 1-30, wherein at least one solubilizer comprises petroleum jelly. 34. The pharmaceutical composition of Claim 33, wherein petroleum jelly is present in an amount from about 20% to about 99.9% of the total weight of the pharmaceutical composition. 34. The pharmaceutical composition of Claim 33, wherein the petroleum jelly is present in an amount from about 70% to about 95% of the total weight of the pharmaceutical composition. 34. The pharmaceutical composition of Claim 33, wherein the petroleum jelly is present in an amount from about 80% to about 90% of the total weight of the pharmaceutical composition. petroleum jelly is about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90% of the total weight of the pharmaceutical composition; is present in an amount of about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9%; 34. A pharmaceutical composition according to claim 33. 38. The pharmaceutical composition of any one of claims 1-37, wherein at least one solubilizer comprises one or more alkanes each independently having at least 9 carbons. The one or more alkanes include nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, tetracosane, or combinations thereof, nonane, decane , undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, icosane, heneicosane, docosane, tricosane, and tetracosane are each independently linear or branched. Pharmaceutical composition as described. The one or more alkanes include nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, or combinations thereof, wherein each of nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, and hexadecane is , independently linear or branched. 39. The pharmaceutical composition of Claim 38, wherein the one or more alkanes is liquid paraffin. 42. The pharmaceutical composition according to any one of claims 38-41, wherein the one or more alkanes are present in an amount from about 0.5% to about 30% of the total weight of the pharmaceutical composition. 42. The pharmaceutical composition according to any one of claims 38-41, wherein the one or more alkanes are present in an amount from about 2% to about 15% of the total weight of the pharmaceutical composition. 42. The pharmaceutical composition of any one of claims 38-41, wherein the one or more alkanes are present in an amount of about 5% to about 10% of the total weight of the pharmaceutical composition. The one or more alkanes is about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 42. The pharmaceutical composition of any one of claims 38-41, present in an amount of 8.5%, about 9%, about 9.5%, or about 10%. The one or more alkanes is about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 42. The pharmaceutical composition of any one of claims 38-41, present in an amount of 8.6%, about 8.7%, about 8.8%, about 8.9%, or about 9%. 47. The pharmaceutical composition of any one of claims 1-46, wherein at least one solubilizer comprises a fatty alcohol having at least 9 carbons. the fatty alcohol is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 48. The pharmaceutical composition of Claim 47, comprising an alcohol having 32, 33, or 34 carbons. 48. The pharmaceutical composition of claim 47, wherein the fatty alcohol comprises alcohols with 12-24 carbons. 48. The pharmaceutical composition of Claim 47, wherein the fatty alcohol is fully saturated or partially saturated. 48. A pharmaceutical composition according to claim 47, wherein the fatty alcohol is stearyl alcohol. 52. The pharmaceutical composition of any one of claims 47-51, wherein the fatty alcohol is present in an amount from about 0.1% to about 15% of the total weight of the pharmaceutical composition. 52. The pharmaceutical composition of any one of claims 47-51, wherein the fatty alcohol is present in an amount from about 1% to about 10% of the total weight of the pharmaceutical composition. fatty alcohol is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5% of the total weight of the pharmaceutical composition; , about 6%, about 6.5%, about 7%, about 7.5%, or about 8%. 47. The pharmaceutical composition of any one of claims 1-46, wherein at least one solubilizer comprises a fatty acid having at least 9 carbons. Fatty acids are 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 56. The pharmaceutical composition of claim 55, comprising , 33, or 34 carbons. 31. The pharmaceutical composition of any one of claims 1-30, wherein the at least one solubilizing agent is petroleum jelly in an amount from about 20% to about 99.9% of the total weight of the pharmaceutical composition. 31. The pharmaceutical composition of any one of claims 1-30, wherein the at least one solubilizer comprises petroleum jelly in an amount of about 90% to about 99.9% of the total weight of the pharmaceutical composition. at least one solubilizer
(i) petroleum jelly in an amount from about 20% to about 99% of the total weight of the pharmaceutical composition;
(ii) liquid paraffin in an amount from about 0.5% to about 30% by total weight of the pharmaceutical composition; and (iii) optionally from about 0.1% to about 15% by total weight of the pharmaceutical composition. 31. The pharmaceutical composition of any one of claims 1-30, comprising stearyl alcohol in an amount up to . the compound is clofazimine and the at least one solubilizer is
(i) petroleum jelly in an amount from about 70% to about 99% by total weight of the pharmaceutical composition; and (ii) liquid paraffin in an amount from about 0.5% to about 30% by total weight of the pharmaceutical composition. 18. The pharmaceutical composition according to any one of claims 1 to 17, comprising a. clofazimine in an amount of about 0.01% to 0.1% of the total weight of the pharmaceutical composition;
b. Vaseline in an amount of about 75% to 85% of the total weight of the pharmaceutical composition;
c. A pharmaceutical composition according to any one of claims 1 to 17, consisting of liquid paraffin in an amount of about 15% to 25% of the total weight of the pharmaceutical composition. a. clofazimine in an amount of about 0.01% to 0.1% of the total weight of the pharmaceutical composition;
b. Vaseline in an amount of about 79% to 80% of the total weight of the pharmaceutical composition; and c. liquid paraffin in an amount of about 20% of the total weight of the pharmaceutical composition;
18. The pharmaceutical composition according to any one of claims 1 to 17, consisting of 61. The pharmaceutical composition of any one of claims 1-60, comprising a stratum corneum penetration enhancer. 64. The pharmaceutical composition of claim 63, wherein the stratum corneum penetration enhancer is polyethoxylated sorbitan monooleate, laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or combinations thereof. 64. The pharmaceutical composition of claim 63, wherein the stratum corneum penetration enhancer is lecithin. 66. The pharmaceutical composition of any one of claims 63-65, wherein the stratum corneum penetration enhancer is present in an amount from about 1% to about 20% of the total weight of the pharmaceutical composition. (a) an active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient has a calculated logP in octanol-water of about 4.0 or greater, or a pharmaceutically acceptable salt thereof; and (b) at least one solubilizer; and (c) at least one stratum corneum penetration enhancer. 68. The pharmaceutical composition of claim 67, wherein the API constitutes about 0.01% to about 10.0% of the total weight of the composition. 69. The pharmaceutical composition of claim 67 or 68, wherein the API logP is from about 4.0 to about 10.0. 69. The pharmaceutical composition of claim 67 or 68, wherein the API logP is from about 7.0 to about 8.0. APIs include hesperetin, lormetazepam, naringenin, cinchonidine, alprenolol, propranolol, ketoprofen, clofibric acid, naproxen, warfarin, apigenin, diazepam, quinine, quetiapine, rosiglitlaurocapram, clotiazepam, tramadol, fenbufen, chlorfena min, pyrilamine , venlafaxine, brompheniramine, diphenhydramine, chrysin, valsartan, penbutolol, diltiazem, ibuprofen, bupivacaine, flurbiprofen, progesterone, chlordiazepoxide, trazodone, haloperidol, glimepiride, abiraterone, indomethacin, clopidogrel, flurazepam, duloxetine, nortriptyline, 69. The pharmaceutical composition according to claim 67 or 68, which is celecoxib, nilotinib, atorvastatin, maprotiline, fluoxetine, diclofenac, amitriptyline, imipramine, loratadine, cyproheptadine, chlorpromazine, sertraline, flufenamic acid, miconazole or rimonabant. the solubilizer is PEG 400, alcohols, polyoxyethylene sorbitan monolaurate, polyethers, ethers, glycol ethers, octyl/decyl mono- and diglycerides, pegylated fatty acid glycerides, fatty acids, fatty acid esters, or any combination thereof; 72. The pharmaceutical composition of any one of claims 67-71. A pharmaceutical composition according to claim 72, wherein the solubilizer is a glycol ether, optionally 2-(2-ethoxyethoxy)ethanol. 74. The pharmaceutical composition of any one of claims 67-73, wherein the stratum corneum penetration enhancer is polyoxyethylene sorbitan monolaurate, laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or combinations thereof. . 75. The pharmaceutical composition of claim 74, wherein the stratum corneum penetration enhancer is a phospholipid. 76. A pharmaceutical composition according to claim 75, wherein the phospholipid is a component of lecithin. 77. The pharmaceutical composition of Claim 76, wherein the lecithin is isolated from egg yolk. (a) clofazimine, or a pharmaceutically acceptable salt thereof;
(b) at least one solubilizer; and (c) at least one stratum corneum penetration enhancer. 79. The pharmaceutical composition of claim 78, wherein clofazimine or a pharmaceutically acceptable salt thereof constitutes up to about 5.0% of the total weight of the composition. 79. The pharmaceutical composition of claim 78, wherein clofazimine or a pharmaceutically acceptable salt thereof constitutes about 0.01% to about 5.0% of the total weight of the composition. 81. The pharmaceutical composition according to any one of claims 78-80, wherein the solubilizer constitutes about 1% to about 60% of the total weight of the composition. 81. The pharmaceutical composition according to any one of claims 78-80, wherein the solubilizer constitutes about 15% to about 25% of the total weight of the composition. the solubilizer is PEG 400, alcohols, polyoxyethylene sorbitan monooleate, polyethers, ethers, glycol ethers, octyl/decyl mono- and diglycerides, pegylated fatty acid glycerides, fatty acids, fatty acid esters, or any combination thereof; 83. The pharmaceutical composition of any one of claims 78-82. 84. A pharmaceutical composition according to claim 83, wherein the solubilizer is a glycol ether. Glycol ethers are 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol, 2-phenoxyethanol, 2-benzyloxyethanol, 1-methoxy-2-propanol, 2- (2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol, 2-(2-propoxyethoxy)ethanol, 2-(2-butoxyethoxy)ethanol, (2-methoxyethoxy)methanol, (2-ethoxy 85. The pharmaceutical composition of claim 84, which is (ethoxy)methanol, (2-propoxyethoxy)methanol, or (2-butoxyethoxy)methanol. Claim 85, wherein the glycol ether is 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol, 2-(2-propoxyethoxy)ethanol, or 2-(2-butoxyethoxy)ethanol The pharmaceutical composition according to . 87. The pharmaceutical composition according to claim 86, wherein the glycol ether is 2-(2-ethoxyethoxy)ethanol. 85. The pharmaceutical composition of claim 84, wherein the glycol ether is dimethoxyethane, diethoxyethane, dipropoxyethane, or dibutoxyethane. 85. The pharmaceutical composition of claim 84, wherein the glycol ether is 2-methoxyethyl acetate, 2-ethoxyethyl acetate, 2-butoxyethyl acetate, or 1-methoxy-2-propanol acetate. 90. The pharmaceutical composition of any one of claims 78-89, wherein the stratum corneum penetration enhancer constitutes from about 1% to about 30% of the total weight of the composition. 90. The pharmaceutical composition of any one of claims 78-89, wherein the stratum corneum penetration enhancer constitutes about 2% to about 8% of the total weight of the composition. 92. The pharmaceutical composition of any one of claims 78-91, wherein the stratum corneum penetration enhancer is polyoxyethylene sorbitan monooleate, laurocapram, phospholipids, ethanol, pegylated fatty acid glycerides, or combinations thereof. . 93. The pharmaceutical composition of claim 92, wherein the stratum corneum penetration enhancer is a phospholipid. 94. The pharmaceutical composition of claim 93, wherein the phospholipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin, lecithin or phosphatidic acid. 95. The pharmaceutical composition of Claim 94, wherein the phospholipid is a component of lecithin. 96. The pharmaceutical composition of Claim 95, wherein the lecithin is isolated from egg yolk. a) 0.01-2% by weight clofazimine, or a pharmaceutically acceptable salt thereof;
79. The pharmaceutical composition of claim 78, comprising b) 5-50% by weight of a solubilizer; and c) 1-20% by weight of a stratum corneum transdermal penetration enhancer. a) clofazimine, or a pharmaceutically acceptable salt thereof, is present in an amount from about 0.01% to about 2.0% of the total weight of the composition;
b) the solubilizer is 2-(2-ethoxyethoxy)ethanol and is present in an amount from about 10% to about 30% of the total weight of the composition;
79. The pharmaceutical composition of Claim 78, wherein c) the stratum corneum penetration enhancer is lecithin and is present in an amount from about 2% to about 19% of the total weight of the composition. a) clofazimine, or a pharmaceutically acceptable salt thereof, is present in an amount from about 0.1% to about 0.5% of the total weight of the composition;
b) the solubilizing agent is 2-(2-ethoxyethoxy)ethanol and is present in an amount from about 15% to about 25% of the total weight of the composition;
79. The pharmaceutical composition of Claim 78, wherein c) the stratum corneum penetration enhancer is lecithin and is present in an amount from about 4% to about 6% of the total weight of the composition. a) clofazimine, or a pharmaceutically acceptable salt thereof, is present in an amount from about 0.1% of the total weight of the composition;
b) the solubilizer is 2-(2-ethoxyethoxy)ethanol and is present in an amount from about 20% of the total weight of the composition;
79. The pharmaceutical composition of Claim 78, wherein c) the stratum corneum penetration enhancer is lecithin and is present in an amount from about 5% of the total weight of the composition. 101. The pharmaceutical composition of any one of claims 78-100, further comprising a preservative. 102. The pharmaceutical composition of claim 101, wherein the preservative is calcium benzoate, chlorobutanol, nipalgin or sorbate. 101. The pharmaceutical composition of any one of claims 67-100, formulated for topical administration. 104. The pharmaceutical composition according to any one of claims 1-103, wherein the formulation is formulated as a gel. 104. The pharmaceutical composition according to any one of claims 1-103, wherein the formulation is formulated as a cream. 104. The pharmaceutical composition according to any one of claims 1-103, wherein the formulation is formulated as an ointment. 107. Any one of claims 1-106, wherein the formulation has an assay value of 90% to 110% w/w, based on initial API content, when stored at about 40°C and 75% RH for 6 months. The pharmaceutical composition according to . 107. Any one of claims 1-106, wherein the formulation has an assay value of 90% to 110% w/w, based on initial API content, when stored at about 25°C and 60% RH for 9 months. The pharmaceutical composition according to . 109. Any one of claims 1-108, wherein the formulation has a total amount of impurities of about 2% w/w or less, based on the initial amount of API, when stored at about 40°C and 75% RH for 6 months. The pharmaceutical composition according to . 109. Any one of claims 1-108, wherein the formulation, when stored at about 25°C and 60% RH for 9 months, has a total amount of impurities of about 2% w/w or less, based on the initial amount of API. The pharmaceutical composition according to . 111. A method of treating skin disorders comprising administering a pharmaceutical composition according to any one of claims 1-110. 112. The method of claim 111, wherein the skin disease is caused by immune inflammation. 113. The method of claim 112, wherein the skin disease is psoriasis, vitiligo, lupus erythematosus, chronic eczema, atopic dermatitis, dermatitis or contact dermatitis. 113. The method of claim 112, wherein the skin disease is atopic dermatitis. 113. The method of claim 112, wherein the skin disease is psoriasis vulgaris. 111. Use of the pharmaceutical composition according to any one of claims 1-110 in the preparation of a medicament for treating skin diseases.

Images